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The HTLV-1 Tax interactome


The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to transcriptional activation, proliferation and ultimately transformation. To carry out these functions, Tax1 interacts with and modulates activity of a number of cellular proteins. In this review, we summarize the present knowledge of the Tax1 interactome and propose a rationale for the broad range of cellular proteins identified so far.

1 Introduction

Human T-lymphotropic viruses (HTLV-1 to -4) belong to the Deltaretrovirus genera of the Orthoretrovirinae subfamily. HTLV-1 was the first discovered human retrovirus in the early eighties [1]. HTLV-2 was described two years later [2] whereas HTLV-3 and -4 subtypes were isolated only recently [3, 4]. HTLV-1 is the etiological agent of an aggressive leukemia called adult T-cell leukemia/lymphoma (ATL) and a neurodegenerative disease, tropical spastic paraparesis/HTLV associated myelopathy (TSP/HAM). Isolated from a case of hairy-cell leukemia, HTLV-2 is by far less pathogenic although its involvement in the development of TSP has been reported [5, 6]. HTLV-3 and -4 have not yet been associated to any pathology, likely due to their recent identification and to the low number of isolates. Three HTLV subtypes have closely related simian viruses (named STLV-1, -2 and -3) while a STLV-5 strain is presently still devoid of a human counterpart [7]. Another related deltaretrovirus, bovine leukemia virus (BLV) is the etiological agent of enzootic bovine leukemia. BLV infection of sheep has been used as an animal model for HTLV [8].

The genome of the HTLV viruses contain typical structural and enzymatic genes (gag, prt, pol and env) flanked by two long terminal repeats (LTRs) but also harbors an additional region called pX located between the env gene and the 3'-LTR. This region contains at least four partially overlapping reading frames (ORFs) encoding accessory proteins (p12I, p13/p30II), the Rex post-transcriptional regulator (ORF III) and the Tax protein (ORF IV). The complementary strand of the HTLV-1 proviral genome is also transcribed, yielding spliced isoforms of the Hbz factor [911]. Hbz interacts with factors JunB, JunD, CREB and CBP/p300 to modulate gene transcription [1214]. There is an inverse relantionship between high Hbz and low Tax expresssion in primary ATL [15].

Among proteins encoded by HTLV-1, Tax1 exerts an essential role in viral transcription as well as in cell transformation [11, 1618]. These pleiotropic functions are directed by a very wide spectrum of interactions with cellular proteins. In this review, we summarize the current knowledge pertaining to the Tax1 interactome and focus more particularly on its impact on transcription, viral persistence and transformation.

2 Interaction of Tax1 with transcription factors and post-transcriptional regulators

In eukaryotes, initiation and elongation of gene transcription requires decondensation of the locus, nucleosome remodeling, histone modifications, binding of transcriptional activators and coactivators to enhancers and promoters and recruitment of the basal transcription machinery to the core promoter [19, 20]. Tax1 is a pleiotropic transcription factor that interferes with several of these mechanisms and modulates transcription of a wide range of cellular genes. In fact, Tax1 deregulates expression of more than one hundred genes [21] through interactions with transcriptional activators, basal transcription factors and proteins involved in chromatin remodeling. Moreover, Tax1 associates with proteins involved post-transcriptionnal control of mRNAs and further modulates gene expression.

2.1 Transcriptional activators and repressors

2.1.1 CREB/ATF factors

Tax1 was initially described as an activator of LTR-directed transcription [22]. Three imperfectly conserved 21-base-pair (bp) repeat sequences called (TxRE) located in the U3 region of the LTR are required and sufficient to confer Tax1 responsiveness [23]. The TxRE element contains an octamer motif TGACG(T/A)(C/G)(T/A) that is flanked by a G stretch and a C stretch at the 5' and 3' sides, respectively [24]. Interestingly this octamer shares homology with the consensus cAMP-responsive element (CRE) 5'-TGACGTCA-3' [24]. Nevertheless, Tax1 exhibits poor affinity for DNA and does not bind directly to the TxRE element [25] but interacts with CRE-binding/activating transcription factors (CREB/ATF). In fact, Tax1 interacts in vitro with a number of proteins of the CREB/ATF family of transcription factors: CREB, CREM, ATF1, ATF2, ATF3, ATF4 (CREB2) and XBP1 (X-box-binding protein 1) [2631]. These proteins share a common cluster of basic residues allowing DNA binding and a leucine zipper (b-Zip) domain involved in homo- and heterodimerization. Dimer formation modulates their DNA binding specificity and transcriptional activity [32]. Biochemical studies revealed that Tax1 promotes formation of a Tax1-CREB/ATF-TxRE ternary complex in vitro by interacting with the b-Zip domain of CREB/ATF factors. Mechanistically, Tax1 enhances the dimerization of CREB/ATF factors, increases their affinity for the viral CRE [3336] and further stabilizes the ternary complex through direct contact of the GC-rich flanking sequences [37, 38]. Tax1 then recruits co-activators (CBP/p300 and P/CAF) to facilitate transcriptional initiation (see 2.3.1). The ability of Tax1 to dimerize is required for efficient ternary complex formation and for optimal transactivation [39, 40]. Interaction of Tax1-CREB/ATF with the LTR promoter DNA was further explored by chromatin immunoprecipitation (ChIP) [41]. In HTLV-1 infected human T-cells (SLB-1), Tax1 and a plethora of CREB/ATF factors as well as other b-Zip proteins bind to the LTR promoter, further confirming interaction in vivo. The fact that Tax1 interacts with ATFx adds another level of complexity since this factor represses Tax1-mediated LTR activation [42]. Tax1 is thus able to interact with positive as well as with negative CREB/ATF factors to modulate LTR promoter-directed activity.

Tax1 also binds to CREB co-activator proteins called transducers of regulated CREB activity (TORCs). In fact, Tax1 interacts with the three members of this family (TORC1, TORC2 and TORC3) [43, 44] and TORCs cooperate with Tax1 to activate the LTR in a CREB and p300-dependent manner. Thus, TORCs are thought to associate with the Tax1 ternary complex and participate to transcriptional activation.

CREB/ATF members play a role in cell growth, survival and apoptosis by regulating CRE-directed gene transcription in response to environmental signals such as growth factors or stress [32, 45]. Furthermore, CREB/ATF proteins also have significant impact on cancer development [45]. Depending on the cell type, Tax1 mutants deficient for CREB activation are incompetent for transformation or induction of aneuploidy [4650]. Tax1 activates a variety of cellular genes through its interactions with CREB/ATF proteins, for example those encoding interleukin 17 or c-fos [51, 52]. Conversely, Tax1 also represses expression of genes like cyclin A, p53 and c-myb by targeting CREB/ATF factors [5355]. Transcriptomic profiling of cells expressing either a wild-type or a CREB-deficient Tax1 protein revealed several cellular genes controlled by CRE elements activated by Tax1 [50]. Among these, Sgt1 (suppressor of G2 allele of SKP1) and p97(Vcp) (valosin containing protein) have functions in spindle formation and disassembly, respectively.

Together, these reports thus demonstrate that Tax1 interacts with a series of CREB/ATF factors and modulates expression of viral and cellular genes through CRE elements. The specific contribution of each CREB/ATF member in Tax1-mediated gene transcription remains unclear.

2.1.2 Serum responsive factor and members of the ternary complex factor

HTLV-1 infected T-cell lines expressing Tax1 display increased expression of AP1 (activator protein 1), a homo- or heterodimeric complex of Fos (c-Fos, FosB, Fra1 and Fra2) and Jun (c-Jun, JunB and JunD) [56, 57]. Fos and Jun are under the transcriptional control of the serum responsive factor (SRF) in response to various stimuli such as cytokines, growth factors, stress signals and oncogenes. SRF binds to the SRF responsive element (SRE) located in the Fos/Jun promoters which contains two binding sites: a CarG box (CC(A/T)6GG) and an upstream Ets box (GGA(A/T)). Once SRF occupies the CArG box, the ternary complex factor (TCF) establishes protein interaction with SRF and subsequently binds the upstream Ets site. This complex then recruits the co-activators P/CAF and CBP/p300 to activate transcription.

In reporter assays, Tax1 activates transcription of promoters under the control of SRE motifs [52, 56, 58] without direct binding to the DNA but through interactions with transcription factors associated with the SRF pathway. Tax1 has been shown to bind directly to SRF [5961] and to various members of the TCF complex such as Sap1 (SRF accessory protein 1), Elk1, Spi1 (spleen focus forming virus (SFFV) proviral integration oncogene 1) and Ets1 [49, 62, 63]. Tax1 interaction with SRF results in increased binding of SRF to the SRE and altered site selection [64]. Once the complexes are stabilized, Tax1 recruits the co-activators CBP/p300 and P/CAF (see 2.3.1) and mediates transactivation [63].

It thus appears that Tax1 activates transcription from CREB- and SRF-responsive sites through a similar mechanism which involves its interaction with transcription factors resulting in enhanced DNA binding, altered site selection and coactivator recruitment [16].

2.1.3 Nuclear factors κB (NF-κB)

HTLV-1 infected cells display increased expression of various cytokines and cytokine receptors such as interleukin 2 (IL2) and the α-subunit of its high-affinity receptor complex (IL2Rα) [6568]. Induction of IL2 and IL2Rα expression is mediated by Tax1 activation of the NF-κB/Rel family of transcription factors [69, 70]. By modulating expression of a wide range of genes involved in apoptosis, proliferation, immune response and inflammation, NF-κB is thought playing a central role in Tax1-mediated cell transformation [16].

In mammals, the NF-κB family of transcription factors is composed of five structurally related members, RelA, RelB (p65), c-Rel, NF-κB1 (p50/p105) and NF-κB2 (p52/p100) which form various dimeric complexes that transactivate or repress target genes bearing a κB enhancer [71, 72]. p105 and p100 are precursor proteins that are processed proteolytically to the mature p50 and p52 forms, respectively. These factors share a common Rel-homology domain (RHD) mediating their dimerization, DNA binding and nuclear localization. In non-activated cells, NF-κB dimers are trapped in the cytoplasm by inhibitory proteins called IκBs such as p105, p100, IκBα, IκBβ and IκBγ (C-terminal region of p105), that mask the nuclear localization signal of NF-κB factors through physical interaction [71, 72]. NF-κB activation involves phosphorylation of IκB inhibitors by the IκB kinase (IKK), which triggers their ubiquitination and subsequent proteasomal degradation, resulting in nuclear translocation of NF-κB dimers [72, 73].

Tax1 associates with RelA, c-Rel, p50 and p52 after their translocation in the nucleus [61, 74, 75] but also directly recruits RelA from the cytoplasm [76, 77]. After interaction with these NF-κB factors, Tax1 increases their dimerization which is essential for binding to target promoters [61, 75, 78]. When the complex is bound to the promoter, Tax1 recruits the CBP/p300 and PCAF co-activators [79, 80], leading to transcriptional activation

2.1.4 Other transcription factors

Tax1 has been shown to associate with CCAAT binding proteins such as NF-YB (nuclear factor YB subunit) and C/EBPβ (CCAAT/enhancer-binding protein β) [8183]. Through its binding to NF-YB, Tax1 activates the major histocompatibility complex class II promoter [82]. Besides, C/EBPβ acts as a transcriptional repressor by preventing Tax1 binding to the LTR [83]. On the other hand, Tax1 increases binding of C/EBPβ to and activates the IL-1β promoter [81]. It is noteworthy that C/EBP factors have been implicated in regulation of cellular proliferation and differentiation but also in tumor formation and leukemia development [84].

Tax1 forms ternary complexes in vitro with Sp1 (specificity protein 1)/Egr1 (early growth response 1) [85] and Sp1/Ets1 [62], thereby participating directly in transcriptional activation of the c-sis/PDGF-B (platelet-derived growth factor B) proto-oncogene and PTHrP (parathyroid hormone-related protein) P2 promoters, respectively. Of note, PTHrP is up-regulated during immortalization of T-lymphocytes by HTLV-1 and plays a primary role in the development of humoral hypercalcemia of malignancy that occurs in the majority of patients with ATL [86, 87].

Tax1 further associates with nuclear respiratory factor 1 (NRF1) and activates the CXCR4 chemokine receptor promoter [88].

Finally, the transcriptional repressor MSX2 (msh homeobox homolog 2) impairs Tax1 mediated transactivation through direct binding [89].

2.2 Basal transcription factors

Tax1 interacts with TFIIA (transcription factor II A) and with two subunits of TFIID: TBP (TATAA-binding protein) and TAFII28 (TBP-associated factor II 28) [9092]. These basal transcription factors compose the preinitiation transcription complex responsible for the recruitment of RNA polymerase II. Owing to this interaction, Tax1 increases the binding of TBP to the TATAA site and further stimulates transcription initiation from the LTR [93].

2.3 Chromatin modifying enzymes

Structural variations of chromatin range from condensed heterochromatin to more open euchromatin, a process that depends on antagonistic effects between multiple protein complexes. Among the complexes affecting chromatin structure, there are those who are capable of altering the histones themselves, the histone deacetylases (HDAC), acetyltransferases (HAT), demethylases (HDM) and methyltransferases (HMT), and those that use the energy of ATP to change the structure of the nucleosome as the SWI/SNF complex [9496]. Tax1 expression and HTLV-1 infection both reduce histone levels in T cells [97]. Moreover, Tax1 interacts directly and recruits several proteins involved in chromatin remodeling to modulate gene transcription. The involvement of Tax1-binding proteins in transcriptional activation has been primarily described in the context of the viral LTR. Nevertheless, similar mechanisms are also likely to participate in the activation of cellular promoters.

2.3.1 HATs

Acetylation of lysine residues located in the N-terminal tails of histone proteins by HATs is a crucial step for activation of gene transcription. Tax1 interacts with several HATs: p300, its homologous CREB binding protein (CBP) and p300/CBP associated factor (P/CAF) [98102]. Tax1 recruits the CBP/p300 and P/CAF once the Tax1-CREB-TxRE complex is stabilized (see 2.1.1), each of which being able to enhance Tax1-mediated transactivation of a transiently transfected LTR reporter. CBP/p300 and P/CAF bind independently on different regions of Tax1 and interaction of Tax1 with these two cofactors is required for optimal transcriptional activity from transiently transfected but also stably integrated LTR reporters [101103]. Surprisingly, P/CAF but not CBP/p300 is able to enhance transcription from the LTR independently of its HAT activity [101, 103]. Tax1 mediates recruitment of CBP/p300 on reconstituted chromatin templates and facilitates transactivation in a HAT-activity dependent manner [104, 105]. CBP/p300 presence at the LTR template correlates with histone H3 and H4 acetylation as well as increased binding of basal transcription factors and RNA polymerase II. ChIP analyses with HTLV-1 infected T cell lines indicate that Tax1, CBP/p300 and acetylated histone H3 and H4 are indeed associated with the LTR promoter [41, 105].

There is a long lasting debate about how Tax1 recruits CBP/p300 at the Tax1-CREB/ATF-TxRE complex. Phosphorylation of CREB at serine 133 by protein kinases A or C is required for CBP/p300 recruitment via physical interaction with the KIX domain [106108]. It has long been suggested that Tax1 bypasses the requirement for CREB phosphorylation to recruit coactivators [98, 100]. Nevertheless, recent reports indicate that Tax1 rather cooperates with phosphorylated CREB (pCREB) to induce transactivation [109, 110]. High levels of pCREB are detected in Tax1 expressing cells and in HTLV-1-infected human T-lymphocytes [110]. Tax1 and pCREB interact simultaneously at two distinct binding sites on the KIX domain forming a very stable complex with the viral CRE [110, 111]. Both CREB phosphorylation and Tax1 binding are needed for efficient interaction of full-length CBP to pCREB and subsequent transcriptional activation [112].

Finally, Tax1 is able to repress the activity of some transcription factors by competitive usage of CBP, p300 and P/CAF. As mentionned above, stable complex formation between Tax1, a transcription factor (e.g. CREB or SRF) and CBP/p300 contributes to transcriptional activation. On the contrary, when Tax1 has poor affinity for a transcription factor (e.g. p53, MyoD or STAT2), it interferes with co-activator recruitment and prevents their activition [113116]. Although controversial, this mechanism termed trans-repression could partipate to p53 inactivation in Tax1 expressing cells and HTLV-1 infected lymphocytes (for a review see [117]).

2.3.2 HDACs

Among three HDACs (-1, -2 and -3) interacting with the viral LTR in HTLV infected cell lines [118], Tax1 binds directly to HDAC1. HDAC1 overexpression represses Tax1-mediated transactivation owing to its HDAC activity [119]. Nevertheless, the presence of Tax1 and HDAC1 on the viral promoter is mutually exclusive [118, 120]. HDAC1 binds to the non-activated LTR and is released from the promoter through physical interaction with Tax1 allowing recruitment of co-activators and transcription initiation. Tax1 is also able to tether HDAC1 to the tyrosine phosphatase SHP1 promoter and selectively down-regulate gene expression [121].

HDACs form multiprotein complexes together with DNA-histone binding proteins such as SMRT (silencing mediator for retinoid and thyroid receptor) and MBD2 (methyl-CpG-binding domain 2) that both interact with Tax1 and are involved in Tax1 transcriptional activities [122, 123]. It thus seems that Tax1, through direct association with HDACs and HDAC-containing complexes is able to selectively activate or repress viral and cellular genes expression.

2.3.3 HMTs and HDMs

Mono-, di- and tri-methylation of histone H3 at lysine 9 (H3K9) play a crucial role in structural modification of chromatin. Tax1 associates with two enzymes involved in regulation of H3K9 methylation: SUV39H1 (suppressor of variegation 3–9 homologue 1), a HMT and JMJD2A (Jumonji containing domain 2A), a HDM [124, 125]. Methylated H3K9 is a hallmark of transcriptionally inactive chromatin whereas demethylation rather promotes transcriptional activation [126]. SUV39H1 interacts with Tax1 and represses Tax1-mediated transactivation of the LTR [124]. JMJD2A is highly expressed in HTLV-1 infected cell lines but its role on Tax1-mediated transcription is currently unknown [125].

Methylation of histone H3 at arginine residues is another important regulatory mechanism of transcriptionnal regulation. Tax1 associates with coactivator-associated arginine methyltransferase (CARM1), which preferentially induces methylation at residues R2, R17 and R26 of histone H3 [127]. CARM1 is recruited by Tax1 to the LTR and increases Tax1-mediated transactivation of the LTR. Consistently, silencing of CARM1 impairs Tax1 transcriptional activation, R2-, R17- and R26-methylated histone H3 proteins being present on the LTR promoter in HTLV-1 infected cells.

Tax1 thus interacts with different histone methyltranferases and demethylases to modulate histone methylation and regulate gene expression.

2.3.4 The SWI/SNF complex

The SWI/SNF (Switch/Sucrose Non Fermentable) complex utilizes the energy of ATP hydrolysis to remodel chromatin structures, thereby allowing transcription factors to gain access to DNA during initiation and elongation steps of transcription [128, 129]. Tax1 interacts with different components of SWI/SNF: BRG1, BAFs 53, 57 and 155 [130]. Overexpression and silencing of BRG1 increments and impedes Tax1 transactivation of the LTR, respectively [130]. It was first suggested that Tax1 targets BRG1/BRM downstream of RNA polymerase II in order to prevent stalling of transcription. This model was apparently contradicted by the capacity of Tax1 to efficiently activate transcription from chromosomally integrated LTR and NF-κB promoter in a BRG1/BRM deficient cell line [131]. Nevertheless, this observation does not exclude that factors of the SWI/SNF complex cooperate with Tax1 to promote gene transcription. Consistent with this idea, Tax1 cooperates with SWI/SNF complex and RNA polymerase II to promote nucleosome eviction during transactivation [132]. Histone eviction increases accessibility of DNA to transcription factors and requires activity of SWI/SNF and RNA polymerase II [128, 133]. Of note, Tax1 may also impact indirectly on SWI/SNF function [134] by interaction with DNA topoisomerase I [135].

Tax1 is thus able to target SWI/SNF complex components to promote nucleosome displacement and participate to transcriptional activation.

2.4 Positive transcription elongation factor b (P-TEFb) and sc35

The switch from initiation of transcription to elongation requires promoter clearance and phosphorylation of the RNA polymerase II carboxyl-terminal domain (CTD) [19]. Phosphorylaton of CTD on serine 5 (S5) and 2 (S2) requires the kinase activities of the basal transcription factor TFIIH and CDK9, respectively. In the cell, CDK9 together with regulatory subunits cyclin T1, -T2, or -K compose the positive transcription elongation factor b (P-TEFb) that ensures the elongation phase of transcription by RNA polymerase II [136, 137]. Tax1 recruits P-TEFb to the viral promoter by interacting with cyclin T1 and CDK9 silencing or depletion inhibits Tax1-mediated transactivation [138, 139]. In fact, recruitment of P-TEFb activity to the LTR promoter increases CTD phosphorylation at serine S2 (but not S5) and allows transcriptional activation [138].

Recent data suggest that the splicing factor sc35 has a critical role in P-TEFb recruitment and positively impacts on transcription [140]. Tax1 binds and colocalizes with sc35 and P-TEFb in nuclear transcriptional hot spots termed speckled structures [141].

2.5 Nuclear receptors

Nuclear receptors (NR) belong to a large family of ligand-activated transcription factors that regulate gene expression in response to steroids, retinoids, and other signaling molecules [142]. Tax1 functions as a general transcriptional repressor of nuclear receptors such as glucocorticoid receptors (GR) [143]. A Tax1-binding protein referred to as Tax1BP1 and identified in a yeast two hybrid screen acts as a transcriptional co-activator for NR. Tax1 represses GR signaling by dissociating Tax1BP1 from the receptor-protein containing complex. Consistently, Tax1BP1 overexpression restores GR signaling in Tax1-expressing cells [144].

2.6 Post-transcriptional and translational regulators

Tax1-directed gene expression is further regulated at the post-transcriptional and translational levels through protein-protein interactions. Among these, Tax1 associates with TTP, Int6 and TRBP.

2.6.1 Tristetraprolin (TTP)

TTP belongs to a family of adenine/uridine-rich element (ARE)-binding proteins that contain tandem CCCH zinc finger RNA-binding domains [145]. TTP is therefore an important player in posttranscriptional regulation of mRNA containing ARE elements. Indeed, TTP delivers ARE-containing mRNAs in discrete cytoplasmic regions, called RNA granules, involved in regulation of translation or decay of these transcripts [146]. The repertoire of ARE-containing genes includes Tumor Necrosis Factor α (TNFα) and Granulocyte Macrophage-Colony-Stimulating Factor (GM-CSF) [145] involved in cell signaling, metabolism, cell proliferation, immune response, death, differentiation and morphogenesis [147].

Tax1 interacts with TTP and redirects TTP from the cytoplasm to the nuclear compartment as well as in a region surrounding the nucleus [148]. Through its interactions with TTP, Tax1 stabilizes TNFα mRNA and indirectly increases TNFα protein expression. This observation is of importance for the cell transformation process induced by HTLV-1, because TNFα overexpression plays a central role in pathogenesis.

2.6.2 Int6 and TRBP

Tax also binds Int6 (Integration site 6) and TRBP (TAR binding protein) that regulate translation and RNA interference, respectively. In fact, Int6 is a subunit of translation initiation factor eIF3, which regulates mRNA binding to the ribosome [149] while TRBP (TAR binding protein) is a componant of RISC (RNA-induced silencing complex) that mediates RNA interference [150]. Currently, the role of these interactions remains unclear.

2.7 A global model of Tax1 transactivation

Most of the data summarized in the former paragraphs relate to transcriptional activation of the LTR by Tax1 although it is likely that similar mechanisms also pertain to cellular promoters. Figure 1 recapitulates the mechanisms of transactivation: Tax1 relieves transcriptional repression through direct interaction with HDAC (i.e. HDAC1) and/or HMT (panel A). Tax1 interacts with CREB/ATF factors (CA) and enhances their binding to the LTR (panel B). When complexes are stabilized on the promoter, Tax1 recruits histone modifying enzymes and chromatin remodelers. This step affects chromatin structure and allows binding of basal transcription factors on the TATA box that is further stabilized by Tax1 interaction with TFIIA, TFIID and TBP (panel C). Once the initiation complex is formed, Tax1 recruits the P-TEFb factor, leading to CTD phosphorylation and processive elongation (panel D). Finally, interaction of Tax1 with SWI/SNF prevents stalling of transcription elongation.

Figure 1

Global model of Tax1 mediated transactivation. Tax1 relieves transcriptional repression of the LTR through direct interaction with HDAC (i.e. HDAC1) and/or HMT (panel A). Tax1 recruits CREB/ATF transcription factors (CA in panel B), histone modifying enzymes and chromatin remodelers (SWI/SNF, P/CAF and CBP/p300). Tax1 then allows binding of basal transcription factors on the TATA box (panel C). Once the initiation complex is formed, Tax1 recruits the P-TEFb factor, leading to CTD phosphorylation and processive elongation (panel D). Finally, interaction of Tax1 with SWI/SNF prevents stalling of transcription elongation. Adapted from [120, 132, 138, 316].

3 Tax1 interaction with proteins involved in cell signaling

3.1 NF-κB signaling

NF-κB can be activated by a series of stimuli such as antigens or cytokines that trigger two alternative pathways (so-called canonical and non-canonical). The canonical pathway is engaged in response to inflammatory stimuli (such as TNF-α and interleukin 1 IL-1), T-cell receptor activation or exposure to lipopolysaccharide (LPS). This pathway begins with the phosphorylation of IκB inhibitors by the IκB kinase (IKK), a complex of IKKα, IKKβ and IKKγ/NEMO (NF-κB Essential Modulator). IKK is activated by a mitogen-activated protein kinase kinase kinase (MAP3K) that phosphorylates the IKKα and IKKβ subunits. Phosphorylation of IκB inhibitors triggers their ubiquitination and subsequent degradation by the 26S proteasome, resulting in nuclear translocation of NF-κB dimers (e.g. p50/relA) [72, 73]. The non-canonical pathway, which can be induced by stimuli such as CD40 ligand, involves IKKα activation upon phosphorylation by NF-κB inducing kinase (NIK). IKKα then phosphorylates the C-terminal region of p100 leading to subsequent processing of the p100/RelB complex into p52/RelB and its translocation into the nucleus [151]. Interestingly, p52/RelB and p50/RelA dimers target distinct κβ enhancers thereby activating different gene subsets.

Tax1 stimulates both canonical and non-canonical pathways and constitutively activates NF-κB in HTLV-1 infected cells [152154]. The above mentionned interactions of Tax1 with NF-κB transcription factors (see 2.1.3) only explains part of Tax1-mediated NF-κB activation since this completion of this process also requires cytoplamic events. In the canonical pathway, Tax1 associates with the IKKγ/NEMO subunit [155, 156] as well as with activating upstream kinases such as MAPK/ERK kinase kinase 1 (MEKK1) and TGF-β activating kinase 1 (TAK1) [157, 158] (see 3.2). Tax1 thus connects activated kinases to the IKK complex and forces the phosphorylation of IKKα and IKKβ leading to degradation of IκBα and IκBβ [155, 156]. In addition, Tax1 binds directly to the IKKα and IKKβ subunits and activates their kinase activity independently of the upstream kinases [159]. Consistently, silencing of MEKK1 and TAK1 does not impair Tax1-induced NF-κB activation [160]. A third level of Tax1 interference with the canonical pathway is its direct binding to IκBs and their degradation independently of IKK phosphorylation [161, 162]. Tax1 further interacts two subunits of the 20S proteasome (HsN3 and HC9), favors anchorage of p105 and accelerates its proteolysis [163]. Tax1 thus leads to IκB degradation at multiple levels, thereby allowing nuclear translocation of NF-κB independently of external stimuli. Besides, activation of the non-canonical pathway by Tax1 requires its interaction with IKKγ and p100 [152, 154]. Through these interactions, Tax1 targets IKKα to p100, induces p100 processing and nuclear translocation of the p52/RelB dimer. It thus appears that IKKγ is an important Tax1 docking site for activation of both pathways.

Post-translationnal modifications of IKKγ such as phosphorylation and K63 ubiquitination fine-tune NF-κB signaling [164, 165] and are modulated by Tax1 through complex formation. In fact, PP2A activates the IKK complex by promoting dephosphorylation of IKKγ serine 68 [166, 167]. Tax1 complexes with PP2A and IKKγ, maintaining the IKK complex in an active state that is required for activating NF-κB [168, 169]. Ubiquitination is targeted by Tax1 through interaction with Ubc13 and Tax1BP1 [170, 171]. Ubc13, an E2 ubiquitin-conjugating enzyme, is required for Tax1 interaction with IKKγ and subsequent NF-κB activation. Tax1BP1 participates to the formation of an ubiquitin-editing complex together with the deubiquitin enzyme (DUB) A20 and plays a pivotal role in termination of NF-κB and JNK signaling by regulating the activity of A20 [171173]. A20 inhibits IKK activation by cleaving K63 linked polyubiquitin chains on tumor necrosis factor receptor (TNFR) signaling-associated factor 6 (TRAF6), receptor interacting protein 1 (RIP1) and IKKγ [174]. By disruption of complex A20-Tax1BP1, Tax1 inactivates DUB function of A20 and prevents downregulation of IKKγ ubiquitination. Consistent with this model, IKKγ is ubiquitinated in Tax1-expressing cells and in a series of HTLV-1 infected cell lines [160, 171] providing a rationale for the constitutive activation of NF-κB pathway.

3.2 Mitogen-activated kinases (MAPKs)

MAPKs are serine/threonine-specific protein kinases that respond to external mitogen stimuli such as growth factors, cytokines or physical stress. MAPK signaling relies on a sequential phosphorylation cascade that goes through MAP kinase kinase kinase (MAP3K) to MAP kinase kinase (MAP2K) and finally to MAPK. The MAPK family includes the extracellular signal-regulated kinase protein homologues 1 and 2 (ERK1/2), ERK5, the c-Jun N-terminal Kinase 1, 2 and 3 (JNK1/2/3) also known as stress-activated protein kinase-1 (SAPK-1), the p38 isoforms (p38α/β/δ), ERK6, ERK3/4 and ERK7/8 [175]. Tax1 interacts with two MAP3Ks: MEKK1 and TAK1 [157, 158].

3.2.1 MEKK1

MEKK1 primarily regulates JNK and ERK1/2 but also contributes to the NF-κB pathway [176, 177]. Tax1 binds to the amino terminus of MEKK1 and stimulates MEKK1 kinase activity [157]. As a result, Tax1 expression increases IKKβ activity, leading to phosphorylation and degradation of IκBα. Dominant negative mutants of both IKKβ and MEKK1 prevent Tax1 activation of the NFκB pathway but, intriguingly, silencing of MEKK1 does not affect Tax1-induced NF-κB activation [160].

3.2.2 TAK1

TAK1 is involved in JNK, TGF-β and NF-κB dependent signaling pathways [178]. TAK1 acts in concert with TAK1 binding proteins (TABs) which link TAK1 to the upstream activating TNF receptor associated factor (TRAFs) proteins. TAK1 phosphorylates IKKβ and MKK6, thereby activating NF-κB and JNK [179].

TAK1 is constitutively activated in Tax1-expressing cells and in HTLV-1 infected lymphocytes [158, 160, 180]. Tax1 activates TAK1 through complexation with TAK1 and TAB2 and connects TAK1 onto the IKK complex thereby stimulating IKK activity [180, 181]. Consistently, overexpression of TAK1 or TAB2 increases Tax1 transactivation of a NF-κB reporter [180, 181]. However, RNA interference of TAK1 suppresses activation of JNK and p38 but not NF-κB. Constitutive activation of TAK1 is thus not absolutely required for NF-κB activation [160, 180]. TAK1 rather participates to JNK signaling, which is constitutively activated in Tax1-expressing cells, in Tax1-transformed murine fibroblasts and in human lymphocytes transformed with HTLV-1 [182185].

3.3 GPS-2

By linking the nuclear co-receptor (NCoR)-HDAC3 complex to intracellular JNK signaling, G protein pathway suppressor 2 (GPS2) suppresses Ras/MAPK signaling and JNK1 activation [183, 186, 187]. Indeed, the NCoR-HDAC3 deacetylase activity represses transcription of genes involved in JNK signaling [187]. Through interaction with GPS2, Tax1 potently inhibits GPS2-mediated inactivation of JNK signaling [183]. Tax1 thus targets multiple proteins (i.e. TAK1 and GPS2) to constitutively activate JNK signaling.

3.4 GTP-binding proteins

The guanine nucleotide-binding proteins GTPases are molecular switches that cycle between active (GTP-bound) and inactive (GDP-bound) states. The G protein family includes Ras-related GTPases (or small GTPases) and heterotrimeric G proteins (α, β and γ subunits) that are activated by G protein-coupled receptors.

3.4.1 Rho GTPases and the cytoskeleton proteins

Tax1 complexes with several members of the small GTPase Rho family such as RhoA, Rac, Gap1m and Cdc42 [130]. Rho GTPases are activated in response to external stimuli (e.g. growth factor, stress, cytokines) and exert a wide range of biochemical functions like cytoskeleton organization, regulation of enzymatic activities as well as gene expression [188]. Notably, Tax1 binds to proteins involved in cytoskeleton structure and dynamics: α-internexin, cytokeratin, actin, gelsolin, annexin and γ-tubulin [130, 189191]. Through these interactions, Tax1 might thus connect Rho GTPases to their targets and affect cytoskeleton organization. Consistent with this idea, Tax1 localizes around the microtubule organization center (MTOC) and in the cell-cell contact region [192]. Thereby, Tax1 provides an intracellular signal that synergizes with ICAM1 engagement to cause the T-cell microtubule polarization and formation of the virological synapse. Through the formation of complexes with both Rho GTPases and their targets, Tax1 could thus favor HTLV-1 cell-to-cell transmission.

Since Rho GTPases modulate a wide range of signaling networks (SRF, JNK, p38 and NF-kB) [188], complex formation with Tax1 is also likely to modulate transcription.

3.4.2 Heterotrimeric Gβ subunit

Heterotrimeric G proteins are the molecular switches that turn on intracellular signaling cascades in response to activation of G protein coupled receptor (GPCR). After binding of an agonist, the activated GPCR induces an exchange of GDP to GTP on the Gα subunit and facilitates the dissociation of GTP-bound Gβγ and Gα subunits [193]. Through its interaction with Gβ, Tax1 affects SDF-1 dependent activation of the CXCR4 GPCR chemokine receptor. Tax1 enhances response to SDF-1 resulting in MAPK pathway over-activation and increased cell chemotaxis. The HTLV-1 associated pathologies (ATL, HAM/TSP and dermatitis) are characterized by invasion and accumulation of infected T-cells in organs such as lymph nodes, central nervous system or dermis [194]. These results thus provide a rationale for the mechanisms of cell migration observed in HTLV-1 associated pathologies.

3.5 Phosphatidylinositol 3-kinase and AP-1

Phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt play a pivotal role in regulation of nutrient metabolism, cell survival, motility, proliferation and apoptosis. The PI3K family comprises eight members divided into three classes according to their sequence homology and substrate preference [195, 196]. PI3K activation results in phosphorylation of Akt at Ser473 which in turn triggers a broad range of regulatory proteins and transcription factors like AP1 [197].

PI3K-Akt is activated in Tax1-transformed murine fibroblasts and is required for cell transformation [198]. Tax1 complexes with the p85α regulatory subunit of PI3K [199] and inhibits activity of the p110α catalytic protein. p85α/p110α belong to the class IA PI3Ks and are activated by receptor tyrosine kinases, by Ras and Rho family GTPases and by Gβγ subunits from heterotrimeric G-proteins [200]. Since monomeric p110 is unstable and is rapidly degraded, activation of p85α/p110α does not involve the complex dissociation but would rather depend on conformational changes [201, 202]. Tax1 targets p85α and disrupts the p85α/p110α complex leading to increased PI3K activity [203], Akt Ser473 phosphorylation, AP1 activation and ultimately cell proliferation. Consistent with this model, ATL cells display constitutive activation of AP1 [199, 204, 205].

3.6 Smad proteins

Transforming growth factor β (TGFβ) inhibits T cell growth in mid-G1 but can also promote tumorigenesis [206]. TGFβ binds to a heterodimeric complex composed of type I (TβRI) and type II (TβRII) serine/threonine kinase receptors [207]. Upon binding of a TGFβ ligand, TβRII recruits and activates TβRI, which, in turn, phosphorylates downstream targets such as Smad proteins (Smad1-2-3-5-8, receptor activated R-Smad). Common mediator Co-Smad (Smad4) containing complexes then translocate to the nucleus and activate transcription of genes under the control of a Smad-binding element. Signal termination is further mediated by inhibitory Smad (I-Smad) Smad6 and Smad7 [207].

Due to constitutive AP1 activation, ATL cells produce high levels of TGFβ in the sera of HTLV-1 infected patients [208]. TGFβ does not inhibit growth of HTLV-1 infected CD4+ cells but affects CD8-dependent response a mechanism that may impact on immune surveillance [209]. Furthermore, TGFβ stimulates cell surface expression of proteins involved in HTLV binding and fusion (Glut1), leading to enhanced virus transmission and production [210, 211].

Tax1 inhibits Smad-dependent signaling, thereby promoting resistance of HTLV-1 infected cells to TGFβ [184, 212, 213]. This inhibition is mediated by Tax1 interaction with the aminoterminus of Smad2, Smad3, and Smad4 [212]. Through these interactions, Tax1 inhibits complexation and DNA binding of Smad3-Smad4 [184, 212]. Furthermore, Tax1 may compete with Smads for the recruitment of CBP/p300 [213].

3.7 Cas-L and p130Cas

Proteins belonging to Crk-associated substrate (Cas) family are multiadaptator and scaffold molecules that spatially and temporally control signal transduction downstream of integrins, receptors protein tyrosine kinase, estrogen receptors and GPCRs. Upon binding of a ligand to these receptors, Cas proteins are tyrosine phosphorylated and recruit adaptors and effectors (such as small GTPase) to activate downstream targets such as JNK and ERK. As a result, Cas proteins regulate cell survival, apoptosis and migration. Furthermore, deregulation of Cas functions has been linked to cell transformation, invasion and cancer [214].

Among Cas proteins, Tax1 associates with p130Cas and CasL (lymphocyte type) [215]. CasL, which is preferentially expressed in lymphocytes [216], is phosphorylated and over-expressed in Tax1-expressing cells, in Tax1-transgenic mice as well as in primary lymphocytes isolated from ATL patients [215, 217]. The Tax1 and CasL interplay results in enhanced motility of Tax1-expressing lymphocytes in response to fibronectin and CD3 [215]. Since CasL also participates in RhoGTPase activation, Tax1 could interconnect cytoskeleton proteins, stimulate cytoskeleton rearrangement and enhance the motility of leukemic cells.

3.8 Global effects of Tax1-mediated deregulation of cell signaling pathways

As schematized on figure 2, Tax1 interactions with a series of components of several signaling pathways (MAPK, JNK, NF-κB, G proteins, AP1 and TGFβ) affect multiple cellular processes among which cellular activation, proliferation, cytoskeleton rearrangement, cell migration and formation of the virological synapse.

Figure 2

Overview of cell signaling proteins targeted by Tax1. Tax1 interacts with components of several signaling pathways (MAPK, JNK, NF-κB, AP-1 and TGF-β) and promotes cellular activation, proliferation, cytoskeleton rearrangement, cell migration and formation of the virological synapse.

4 Interaction of Tax1 with cell cycle associated proteins

4.1 Cyclin D-CDK4/6 complexes, Rb and CDK inhibitors

Cell cycle progression is a tightly regulated process controlled by cyclins associated with cyclin-dependent kinases (CDK). Cyclins D and E cooperate with CDK4/6 and CDK2 to mediate passage through G1 phase and G1/S transition, respectively [218]. Cyclin D-CDK4/6 and Cyclin E-CDK2 complexes target the Rb retinoblastoma protein (Figure 3). In its hypophosphorylated form, Rb is bound to the transcription factor E2F1, and upon phosphorylation, Rb frees E2F1, which activates transcription of genes required for transition from G1 to S. G1/S progression can be inhibited by CDK inhibitors (CDKI) such as p15INK4b, p16INK4a, p18INK4c and p19INK4d by preventing cyclin D/CDK4/6 complex formation. Tax1 reprograms cell cycle progression, particularly at G1/S transition, through different mechanisms pertaining to transcriptional activation or repression, post-translational modifications and protein-protein interactions [219, 220].

Figure 3

Effect of Tax1 on cell cycle progression. Through a series of interactions with cell-cycle associated proteins, Tax1 accelerates G1/S transition (A), attenuates Chk1/2 activity (B), induces supernumerary centrosomes and impedes SAC (spindle assembly checkpoint) activity (C).

Tax1 is able to interact with cyclins-D1, -D2 and -D3 as well as with CDK4 and CDK6 but not with CDK1 or CDK2 [221224]. Through these interactions, Tax1 stabilizes the cyclin D2/CDK4 complex and enhances its kinase activity, leading to hyperphosphorylation of retinoblastoma protein (Rb). Tax1 also associates with p15INK4b and p16INK4a and counteracts their inhibitory activity of CDK4 [225228]. Finally, Tax1 binds to and targets Rb for proteosomal degradation [229]. Consistently, HTLV-1 infected cell lines and freshly isolated ATL cells display decreased levels of Rb protein.

Figure 3A illustrates Tax1 interactions with components of the cyclin D/CDK complexes and provides a mechanistic model for increased G1-S phase transition efficiency as well as the accelerated cell proliferation measured in vivo [230, 231].

4.2 DNA repair pathway associated proteins

DNA insults and replication stress activate the DNA damage response (DDR) pathway in S and G2/M phases of the cell cycle. Activation of the DDR pathway leads to cell cycle delay or even apoptosis of severely damaged cells, and activates the DNA repair pathway. ATM (Ataxiatelangiectasia mutated) and ATR (ATM-Rad3) proteins and their respective downstream targets Chk2 (checkpoint kinase 2) and Chk1 (checkpoint kinase 1) proteins play a central role in the DDR pathway [232]. In mammals, Chk1 and Chk2 regulate Cdc25, Wee1 and p53 that ultimately inactivate CDKs which inhibit cell-cycle progression. Double-strand breaks usually activate the ATM/Chk2-dependent pathway whereas ATR/Chk1 responds to a wide variety of lesions and replication blocks [233, 234].

Tax1-expressing and ATL cells display DNA damages suggesting that Tax1 abrogates cellular checkpoint and DNA repair [235237]. Tax1 binds Rad51 [130] and DNA Topoisomerase 1 [135] that are both directly involved in DNA repair processes [232, 238]. Moreover, Tax1 associates and colocalizes with Chk1 and Chk2 proteins [239242]. De novo Tax1 expression causes phosphorylation of Chk2 resulting in accumulation of cells in S-G2/M [239, 243]. However, upon gamma irradiation, Tax1 inhibits Chk1 and Chk2 kinase activities and attenuates G2/M arrest and apoptosis, respectively [240, 241]. Tax1 thus activates and represses checkpoint controls depending on the experimental conditions (figure 3B). In fact, Tax1 sequesters phosphorylated Chk2 within chromatin after gamma irradiation-induced DNA-damage [242]. Tax1 thereby impedes phosphorylated Chk2 chromatin egress, a mechanism required for further signal amplification and transmission [244]. Tax1 thus targets multiple components of DNA damage repair pathway and promotes DNA abnormalities.

4.3 Centrosome associated proteins and spindle assembly checkpoint

One of the hallmarks of Tax1-expressing cells particularly in ATL is chromosomal instability and severe aneuploidy [235], suggesting that mechanisms monitoring chromosomal segregation during mitosis are subverted by Tax1. Tax1 interacts with 4 proteins involved in centrosome amplification or in mitotic spindle assembly checkpoint (SAC) (Figure 3C).

4.3.1 RanBP1 and Tax1BP2

The presence of two centrosomes at mitosis is crucial for formation of bipolar mitotic spindles and correct chromosome segregation. Multipolar mitosis which happens when more than two centrosomes emerge in one cell is a possible cause of aneuploidy in solid tumors and leukemias [245]. Supernumerary centrosomes are observed in approximately 30% of ATL cells [246248]. Tax1 colocalizes with the centrosome during mitosis and causes centrosome amplification through physical interaction with Ran/Ran Binding protein 1 (RanBP1) and Tax1BP2 [249, 250]. RanBP1 is involved in the Ran GTP cycle that controls microtubule nucleation and/or stabilization and centrosome cohesion during mitosis [251, 252]. Centrosome fragmentation requires direct Tax1/RanBP1 interaction and Tax1's ability to transactivate NF-κB. Tax1BP2 is thought to act as an intrinsic block to centrosome overreplication [253]. Consistently, overexpression of Tax1BP2 abolishes Tax1-induced centrosome amplification. On the other hand, a Tax1 mutant unable to bind to Tax1BP2 is impaired in centrosome overreplication [250].

4.3.2 Mad1 and cdc20

In eukaryotes, the mitotic spindle assembly checkpoint (SAC) monitors the fidelity of chromosome segregation [254]. SAC functioning requires complex formation between Mad1-2-3 and Bub1-2-3 proteins that arrest mitosis in response to microtubule damage [255]. At the molecular level, SAC activation involves formation of inhibitory complexes between Mad2 and/or Mad3/BubR1 and Cdc20, preventing Cdc20 from activating the anaphase promoting complex/cyclosome (APC/C). APC/C is active during mitosis where it mediates ubiquitination and degradation of an inhibitory chaperone of separase called securin. Once liberated from its inhibitor, separase triggers anaphase by hydrolysing cohesin leading to subsequent separation of sister chromatin. Furthermore, APC/C regulates the degradation of mitotic cyclin, activates CDK1 and, ultimately, promotes mitotic exit [256].

Through physical interactions with Mad1 and Cdc20, Tax1 subverts activation of SAC and APC/C. Tax1 inhibits Mad1 homodimerization, a process that is required for formation of a inhibitory complex between Mad2 and Cdc20 [257259]. Consistently, ATL cells exhibit a defect in the mitotic spindle assembly checkpoint [257]. On the other hand, Tax1 associates with and activates Cdc20-associated APC/C leading to unscheduled degradation of securin and cyclin B1, a delay or failure in mitotic entry and progression, and faulty chromosome transmission [260, 261]. Tax1-induced premature activation of APC/C provokes permanent G1 arrest and senescence [262, 263]. Finally, coexpression of Tax1 and securin enhances chromosomal instability and favors cell transformation in vitro and in vivo [264].

5 Interaction of Tax1 with PDZ-containing proteins

The PSD-95/Drosophila Discs Large/Zona Occludens-I (PDZ) domain containing proteins form signaling complexes at the inner surface of the cell membrane and are involved in a very broad range of functions like cell signaling, adhesion, tight-junction integrity, molecular scaffolding for protein complexes and tumor suppression [265267]. Numerous PDZ proteins have been shown to form a complex with Tax1 owing to its PDZ binding motif (PBM) located in the C-terminus (ETEV) [268]: Pro-IL16 (precursor of interleukin 16) [269], hDLG (Drosophila Discs Large) [270, 271], PSD-95, beta-syntrophin, lin-7 [268], Tip1 (Tax1 Interaction protein 1) [272], MAGI3 (Membrane Associated Guanylate kinase with inverted orientation 3) [273], hTid1 [274] and hScrib [275]. Interaction of Tax1 with these PDZ proteins frequently leads to their delocalization [273, 275, 276]. Functionally, PDZ proteins such as hTid1 and hScrib participate to Tax1-mediated activation of NF-κB and NFAT pathways, respectively [274, 275].

A Tax1-binding protein, hDLG, has been particularly studied owing to its ability to act as a tumor suppressor. hDLG acts downstream of the Wnt/frizzled pathway and binds to the adenomatous polyposis complex (APC) which mediates cell cycle progression [277, 278]. APC-hDLG complex formation negatively regulates G1 to S transition and plays an important role in transducing the APC cell cycle blocking signal [277]. Besides, hDLG is also involved in maintenance and modulation of T cell polarity [279]. Through PBM/PDZ domain interaction, Tax1 induces hyperphosphorylation of hDLG, affects its localization [276] and prevents its binding to APC [271]. Interestingly, hDLG inactivation increases the ability of Tax1 to transform a mouse T-cell line [280].

The Tax1 PBM is critically involved in transformation of rat fibroblasts and IL2 independent growth of mouse lymphocytes [276, 281] and to promote virus-mediated T-cell proliferation in vitro and persistence in vivo [282]. In contrast, HTLV-2 Tax2 protein which does not harbor a PBM has a lower transforming activity than Tax1 [283].

6 Tax1 interaction with nuclear pore and secretory pathway proteins

Tax1 shuttles between the cytoplasm and the nucleus by virtue of a nuclear localization sequence (NLS) and a nuclear export signal (NES) [284286]. In the nucleus, Tax1 is primarily located in interchromatin granules or spliceosomal speckles [141]. In the cytoplasm, Tax1 localizes to organelles associated with the cellular secretory process including the endoplasmic reticulum and Golgi complex [192, 287]. Tax1 is also secreted in the supernatant of HTLV-1 infected cells isolated from HAM-TSP patients [287289] and may behave as an extracellular cytokine. Tax1 shuttling is mediated through interaction with proteins involved in nuclear import, cytoplasmic export and secretory pathways [289293].

6.1 Nucleoporins

Nucleoporins of the nuclear pore complex (NPC) form a channel spanning the double lipid bilayer of the nuclear envelope. Nuclear pore complexes allow passive diffusion of ions and small proteins but translocation of cargoes larger than 40 kDa generally requires specific transport proteins [294]. Import of cargo proteins containing a classical NLS is mediated by the importin α/β dimer and requires metabolic energy which is provided by Ran GTP [295]. In contrast, carrier-independent translocation of proteins into the nucleus is energy independent and requires direct interactions with nucleoporins [295].

Nuclear import and export of Tax1 are both carrier and energy independent but relies on the interaction between Tax1 and the p62 nucleoporin [290]. This interaction is mediated by the aminoterminal zinc-finger motif of Tax1. Consistently, mutations within this motif abolishes Tax1 interaction with p62 and nuclear import [290].

6.2 Proteins involved in Tax1 nuclear export and secretion

Proteins containing a NES domain like Tax1 are expected to interact with the chromosome region maintenance 1 protein (CRM1), a member of the importin β family [296]. Under stress conditions (i.e. UV irradiation), Tax1 interacts with CRM1 and is exported outside of the nucleus, a mechanism that is inhibited by leptomycin B [291, 292]. In the absence of stress however, leptomycin B does not alter subcellular distribution of Tax1 [286], suggesting that Tax1 is not exclusively exported through the CRM1 pathway.

Tax1 nucleo-cytoplasmic shuttling and secretion is directed by associations with proteins involved in nuclear export (calreticulin, RanBP2, p97), in ER to Golgi transport (the coat proteins (COP) βCOP and COPII) and in movement from Golgi to plasma membrane (secretory carrier membrane protein 23 (SNAP23), secretory carrier membrane protein 1 and 2 (SCAMP1, SCAMP2)) [289, 293, 297]. Calreticulin, which is overexpressed in HTLV-1 infected cells, functions similarly to CRM1 by transporting proteins via NES interactions [293, 298]. Tax1 secretion involves a secretory signal located in the C-terminal domain and requires interaction with SNAP23, SCAMP1 and COPII [289].

Tax1 thus targets different cellular factors involved in protein transport to shuttle between nucleus, cytoplasm and extracellular environment.

7 Binding domains in Tax1

To interact with such a broad range of cellular targets, Tax1 contains multiple protein-binding domains (Figure 4). Among these, the N-terminal zinc finger motif associates with transcription factors (CREB/ATF [299], TBP [90], Ets1 [62], NF-YB [82], Egr1 [85]), cyclins [221], nucleoproteins (p62) [290], proteasome subunits [163] and phosphatase PP2A [168]. Mutations within this zinc finger affects Tax1-mediated CREB transactivation as well as subcellular localization due to the presence of a NLS [284]. A domain encompassing residues 55 to 95 regulate interaction of Tax1 with CBP/p300, Chk2 and Gβ2 [102, 241, 300]. The middle of Tax1 harbors a region required for dimerization, two leucine zipper-like motifs (aa 116–145 and 213–248) [39, 301, 302] and a NES sequence [291]. Substitutions within the first leucine zipper (such as T130A and L131S in mutant M22) affect Tax1 interactions with NF-κB [157, 301], proteasome subunits [163] and PP2A [168]. Another mutation (S132A) abolishes Tax1 binding to coil-coiled domain containing proteins [303] (i.e. Mad1, Tax1BP1, Tax1BP2 and GPS2). A region located between the two leucine zippers is required for interaction with CARM-1, Chk2 and Gβ2 [127, 241, 300]. Amino acids 233–246, located within the second leucine zipper regulates Tax1 association with p15INK4b [228], p16INK4a [226], DNA topoisomerase [135] and IκBγ [161]. Consistently, the central region of Tax1 is indeed involved in NF-κB activation. Finally, the carboxyterminal region of Tax1 contains an activation domain (residues 289–332) [304] as well as motifs required for Tax1 localization within the Golgi (residues 312–315) and secretion (residues 330–332) [297]. The carboxyterminal domain is involved in Tax1 binding to Rb [229], PI3K [199], P/CAF [102], P-TEFb [138] and PDZ containing-proteins [268]. In particular, Tax1 mutant M47 (L319R, L320S) is impaired for interaction with P/CAF[102].

Figure 4

Functional regions of Tax1 and interaction domains. NLS (nuclear localization sequence), NES (nuclear export sequence), G (Golgi localization motif), S (secretion motif), LZR (leucine-zipper-like region), P (PDZ binding domain). Adapted from [130].

8 Conclusion

The most intriguing point relating to the Tax1 interactome is the very high number of cellular proteins to which this viral oncogene is able to interact. Today, about 100 Tax1-binding proteins are identified (Table 1) and this number is permanently growing (see for regular updates). Is it possible that a single protein modulates such a wide variety of functions? Are these interactions all relevant for the viral life cycle or pathogenesis? As schematized on Figure 5, the vast majority of these interactions contributes to viral or cellular gene expression and promotes infected cell proliferation or survival, required for maintaining viral load in vivo [231, 305]. On the other hand, checkpoint abrogation allows proliferation of cells with DNA lesions and progressive accumulation of chromosomal abnormalities as frequently observed in ATL [220]. Even if one might entertain doubts about the biological relevance of some Tax1 partners, the Tax1 interactome as a whole likely contributes to the viral life cycle as well as to development of pathogenesis.

Figure 5

Overview of the Tax1 interactome.

Table 1 Cellular proteins interacting with Tax1

Other viral oncogenes such as Kaposi's sarcoma-associated herpesvirus-encoded LANA and adenovirus E1A also interact with numbers of cellular proteins (e.g. more than 40 for E1A and 100 for LANA) [306, 307]. Interestingly, some of these proteins are targeted both by Tax1 and E1A (such as ATF, CBP, p300 or Smad), indicating that similar signaling pathways are involved in distinct viral systems to achieve cell transformation. In particular, Tax1 and E1A share common properties that include regulation of transcriptional activation, chromatin remodeling, interference with p53 activity, regulation of proteasome function and cooperation with Ras in cell transformation [308].

How are these different activities controlled temporarily and spatially? Additional studies are definitely required to address this point. Currently, Tax1 is known to shuttle between cytoplasm and nucleus, to form intranuclear speckles along with a series of cellular proteins (e.g. NF-κB factors [309], sc35 [141] and chk2 [239]) and to target specialized structures such as the centrosome [249, 250]. Moreover, Tax1 localisation and protein interactions are altered under stress conditions [291, 292].

Despite numbers of attempts, Tax1 3-D crystallographic structure is intriguingly still unsolved suggesting that Tax1 adopts a rather undefined conformation. In this context, the concept of intrinsically disordered proteins (IDP) has recently emerged [310]. IDPs contrast to "ordered" proteins that fold into a unique and structured state, which represents a kinetically accessible and energetically favorable conformation. IDP proteins contain one or multiple disordered regions that exist as dynamic ensembles in which atom positions and backbone Ramachandran angles vary significantly with no specific equilibrium values [310]. The presence of short (< 30 residues) and long (> 30 residues) ID regions confer conformationnal flexibility thereby facilitating post-translational modifications and enabling a protein to functionally interact with many cellular partners [310, 311]. Consistently, IDPs are frequently highly connected 'hubs' in the protein-protein networks [311313]. In fact, Tax1 contains many proline (n = 40), serine (n = 25) and glycine (n = 25) residues that are known to promote disorder [310]. According to the VSL1 prediction programme (PONDR®,, Tax1 contains multiple ID regions (n = 6) (Figure 6). In particular, Tax1 contains a long disordered region (spanning amino-acids 76 to 121), in contrast to the well structured capsid (p24), transmembrane (gp21) and surface (gp46) proteins (data not shown). Interestingly, other viral oncogenes such as HPV E6 and E7 are also predicted to contain significant intrinsic disorder [314].

Figure 6

Identification of disordered regions in Tax1 according to the VSL1 algorithm. (PONDR®, A domain encompassing residues 76 to 121 (black bar) corresponds to a long disordered region within Tax1.

On the other hand, Tax1 is modified by phosphorylation, ubiquitination and sumoylation that potentially modulate its functions, localisation and interactions [76, 315]. Tax1 also contains 8 cysteines that may form disulfite bonds or coordinate zinc ions and 48 leucines that are considered as order-promoting residues [310]. Tax1 thus appears as a flexible structure formed by a series of small modular domains that are relatively independent of surrounding sequences and that permits wide conformational changes depending upon its subcellular environment.

We propose that, similarly to the hubs, the ID-based structure of Tax1 allows a wide variety of conformational changes enabling binding diversity and recognition of differently shaped protein partners. Flexible accommodation at various binding interfaces would then allow interaction of more structured domains such as the Tax1 zinc finger and leucine containing helices. This hypothetical model provides a rationale to the very broad range of Tax1 interacting proteins identified so far.

In conclusion, the Tax1 interactome network with the associated biochemical studies reported here provides a molecular basis for understanding viral persistence and pathogenesis, paving the way for the design of compounds to antagonize its ability to mediate cell transformation.


  1. 1.

    Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC: Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980, 77: 7415-7419.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. 2.

    Kalyanaraman VS, Narayanan R, Feorino P, Ramsey RB, Palmer EL, Chorba T, McDougal S, Getchell JP, Holloway B, Harrison AK, .: Isolation and characterization of a human T cell leukemia virus type II from a hemophilia-A patient with pancytopenia. EMBO J. 1985, 4: 1455-1460.

    PubMed Central  CAS  PubMed  Google Scholar 

  3. 3.

    Calattini S, Chevalier SA, Duprez R, Bassot S, Froment A, Mahieux R, Gessain A: Discovery of a new human T-cell lymphotropic virus (HTLV-3) in Central Africa. Retrovirology. 2005, 2: 30-

    PubMed Central  PubMed  Google Scholar 

  4. 4.

    Wolfe ND, Heneine W, Carr JK, Garcia AD, Shanmugam V, Tamoufe U, Torimiro JN, Prosser AT, Lebreton M, Mpoudi-Ngole E, McCutchan FE, Birx DL, Folks TM, Burke DS, Switzer WM: Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters. Proc Natl Acad Sci U S A. 2005, 102: 7994-7999.

    PubMed Central  CAS  PubMed  Google Scholar 

  5. 5.

    Feuer G, Green PL: Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2. Oncogene. 2005, 24: 5996-6004.

    PubMed Central  CAS  PubMed  Google Scholar 

  6. 6.

    Araujo A, Hall WW: Human T-lymphotropic virus type II and neurological disease. Ann Neurol. 2004, 56: 10-19.

    PubMed  Google Scholar 

  7. 7.

    Liegeois F, Lafay B, Switzer WM, Locatelli S, Mpoudi-Ngole E, Loul S, Heneine W, Delaporte E, Peeters M: Identification and molecular characterization of new STLV-1 and STLV-3 strains in wild-caught nonhuman primates in Cameroon. Virology. 2008, 371: 405-417.

    CAS  PubMed  Google Scholar 

  8. 8.

    Gillet N, Florins A, Boxus M, Burteau C, Nigro A, Vandermeers F, Balon H, Bouzar AB, Defoiche J, Burny A, Reichert M, Kettmann R, Willems L: Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human. Retrovirology. 2007, 4: 18-

    PubMed Central  PubMed  Google Scholar 

  9. 9.

    Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM: The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol. 2002, 76: 12813-12822.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. 10.

    Cavanagh MH, Landry S, Audet B, Arpin-Andre C, Hivin P, Pare ME, Thete J, Wattel E, Marriott SJ, Mesnard JM, Barbeau B: HTLV-I antisense transcripts initiating in the 3'LTR are alternatively spliced and polyadenylated. Retrovirology. 2006, 3: 15-

    PubMed Central  PubMed  Google Scholar 

  11. 11.

    Matsuoka M, Jeang KT: Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer. 2007, 7: 270-280.

    CAS  PubMed  Google Scholar 

  12. 12.

    Hivin P, Basbous J, Raymond F, Henaff D, Arpin-Andre C, Robert-Hebmann V, Barbeau B, Mesnard JM: The HBZ-SP1 isoform of human T-cell leukemia virus type I represses JunB activity by sequestration into nuclear bodies. Retrovirology. 2007, 4: 14-

    PubMed Central  PubMed  Google Scholar 

  13. 13.

    Kuhlmann AS, Villaudy J, Gazzolo L, Castellazzi M, Mesnard JM, Duc DM: HTLV-1 HBZ cooperates with JunD to enhance transcription of the human telomerase reverse transcriptase gene (hTERT). Retrovirology. 2007, 4: 92-

    PubMed Central  PubMed  Google Scholar 

  14. 14.

    Clerc I, Polakowski N, Andre-Arpin C, Cook P, Barbeau B, Mesnard JM, Lemasson I: An interaction between the HTLV-1 bZIP factor (HBZ) and the KIX domain of p300/CBP contributes to the downregulation of Tax-dependent viral transcription by HBZ. J Biol Chem. 2008

    Google Scholar 

  15. 15.

    Usui T, Yanagihara K, Tsukasaki K, Murata K, Hasegawa H, Yamada Y, Kamihira S: Characteristic expression of HTLV-1 basic zipper factor (HBZ) transcripts in HTLV-1 provirus-positive cells. Retrovirology. 2008, 5: 34-

    PubMed Central  PubMed  Google Scholar 

  16. 16.

    Grassmann R, Aboud M, Jeang KT: Molecular mechanisms of cellular transformation by HTLV-1 Tax. Oncogene. 2005, 24: 5976-5985.

    CAS  PubMed  Google Scholar 

  17. 17.

    Nerenberg M, Hinrichs SH, Reynolds RK, Khoury G, Jay G: The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science. 1987, 237: 1324-1329.

    CAS  PubMed  Google Scholar 

  18. 18.

    Pozzatti R, Vogel J, Jay G: The human T-lymphotropic virus type I tax gene can cooperate with the ras oncogene to induce neoplastic transformation of cells. Mol Cell Biol. 1990, 10: 413-417.

    PubMed Central  CAS  PubMed  Google Scholar 

  19. 19.

    Lee TI, Young RA: Transcription of eukaryotic protein-coding genes. Annu Rev Genet. 2000, 34: 77-137.

    CAS  PubMed  Google Scholar 

  20. 20.

    Smale ST, Kadonaga JT: The RNA polymerase II core promoter. Annu Rev Biochem. 2003, 72: 449-479.

    CAS  PubMed  Google Scholar 

  21. 21.

    Ng PW, Iha H, Iwanaga Y, Bittner M, Chen Y, Jiang Y, Gooden G, Trent JM, Meltzer P, Jeang KT, Zeichner SL: Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-kappaB activation. Oncogene. 2001, 20: 4484-4496.

    CAS  PubMed  Google Scholar 

  22. 22.

    Felber BK, Paskalis H, Kleinman-Ewing C, Wong-Staal F, Pavlakis GN: The pX protein of HTLV-I is a transcriptional activator of its long terminal repeats. Science. 1985, 229: 675-679.

    CAS  PubMed  Google Scholar 

  23. 23.

    Brady J, Jeang KT, Duvall J, Khoury G: Identification of p40x-responsive regulatory sequences within the human T-cell leukemia virus type I long terminal repeat. J Virol. 1987, 61: 2175-2181.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. 24.

    Jeang KT, Boros I, Brady J, Radonovich M, Khoury G: Characterization of cellular factors that interact with the human T-cell leukemia virus type I p40x-responsive 21-base-pair sequence. J Virol. 1988, 62: 4499-4509.

    PubMed Central  CAS  PubMed  Google Scholar 

  25. 25.

    Giam CZ, Xu YL: HTLV-I tax gene product activates transcription via pre-existing cellular factors and cAMP responsive element. J Biol Chem. 1989, 264: 15236-15241.

    CAS  PubMed  Google Scholar 

  26. 26.

    Zhao LJ, Giam CZ: Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator, Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-protein interaction. Proc Natl Acad Sci U S A. 1992, 89: 7070-7074.

    PubMed Central  CAS  PubMed  Google Scholar 

  27. 27.

    Low KG, Chu HM, Schwartz PM, Daniels GM, Melner MH, Comb MJ: Novel interactions between human T-cell leukemia virus type I Tax and activating transcription factor 3 at a cyclic AMP-responsive element. Mol Cell Biol. 1994, 14: 4958-4974.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. 28.

    Bantignies F, Rousset R, Desbois C, Jalinot P: Genetic characterization of transactivation of the human T-cell leukemia virus type 1 promoter: Binding of Tax to Tax-responsive element 1 is mediated by the cyclic AMP-responsive members of the CREB/ATF family of transcription factors. Mol Cell Biol. 1996, 16: 2174-2182.

    PubMed Central  CAS  PubMed  Google Scholar 

  29. 29.

    Reddy TR, Tang H, Li X, Wong-Staal F: Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4). Oncogene. 1997, 14: 2785-2792.

    CAS  PubMed  Google Scholar 

  30. 30.

    Franklin AA, Kubik MF, Uittenbogaard MN, Brauweiler A, Utaisincharoen P, Matthews MA, Dynan WS, Hoeffler JP, Nyborg JK: Transactivation by the human T-cell leukemia virus Tax protein is mediated through enhanced binding of activating transcription factor-2 (ATF-2) ATF-2 response and cAMP element-binding protein (CREB). J Biol Chem. 1993, 268: 21225-21231.

    CAS  PubMed  Google Scholar 

  31. 31.

    Ku SC, Lee J, Lau J, Gurumurthy M, Ng R, Lwa SH, Lee J, Klase Z, Kashanchi F, Chao SH: XBP-1, a novel human T-lymphotropic virus type 1 (HTLV-1) tax binding protein, activates HTLV-1 basal and tax-activated transcription. J Virol. 2008, 82: 4343-4353.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. 32.

    Hai T, Hartman MG: The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene. 2001, 273: 1-11.

    CAS  PubMed  Google Scholar 

  33. 33.

    Perini G, Wagner S, Green MR: Recognition of bZIP proteins by the human T-cell leukaemia virus transactivator Tax. Nature. 1995, 376: 602-605.

    CAS  PubMed  Google Scholar 

  34. 34.

    Wagner S, Green MR: HTLV-I Tax protein stimulation of DNA binding of bZIP proteins by enhancing dimerization. Science. 1993, 262: 395-399.

    CAS  PubMed  Google Scholar 

  35. 35.

    Anderson MG, Dynan WS: Quantitative studies of the effect of HTLV-I Tax protein on CREB protein--DNA binding. Nucleic Acids Res. 1994, 22: 3194-3201.

    PubMed Central  CAS  PubMed  Google Scholar 

  36. 36.

    Yin MJ, Gaynor RB: HTLV-1 21 bp repeat sequences facilitate stable association between Tax and CREB to increase CREB binding affinity. J Mol Biol. 1996, 264: 20-31.

    CAS  PubMed  Google Scholar 

  37. 37.

    Kimzey AL, Dynan WS: Specific regions of contact between human T-cell leukemia virus type I Tax protein and DNA identified by photocross-linking. J Biol Chem. 1998, 273: 13768-13775.

    CAS  PubMed  Google Scholar 

  38. 38.

    Lundblad JR, Kwok RP, Laurance ME, Huang MS, Richards JP, Brennan RG, Goodman RH: The human T-cell leukemia virus-1 transcriptional activator Tax enhances cAMP-responsive element-binding protein (CREB) binding activity through interactions with the DNA minor groove. J Biol Chem. 1998, 273: 19251-19259.

    CAS  PubMed  Google Scholar 

  39. 39.

    Jin DY, Jeang KT: HTLV-I Tax self-association in optimal trans-activation function. Nucleic Acids Res. 1997, 25: 379-387.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. 40.

    Tie F, Adya N, Greene WC, Giam CZ: Interaction of the human T-lymphotropic virus type 1 Tax dimer with CREB and the viral 21-base-pair repeat. J Virol. 1996, 70: 8368-8374.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. 41.

    Lemasson I, Polakowski NJ, Laybourn PJ, Nyborg JK: Transcription factor binding and histone modifications on the integrated proviral promoter in human T-cell leukemia virus-I-infected T-cells. J Biol Chem. 2002, 277: 49459-49465.

    CAS  PubMed  Google Scholar 

  42. 42.

    Forgacs E, Gupta SK, Kerry JA, Semmes OJ: The bZIP transcription factor ATFx binds human T-cell leukemia virus type 1 (HTLV-1) Tax and represses HTLV-1 long terminal repeat-mediated transcription. J Virol. 2005, 79: 6932-6939.

    PubMed Central  CAS  PubMed  Google Scholar 

  43. 43.

    Koga H, Ohshima T, Shimotohno K: Enhanced activation of tax-dependent transcription of human T-cell leukemia virus type I (HTLV-I) long terminal repeat by TORC3. J Biol Chem. 2004, 279: 52978-52983.

    CAS  PubMed  Google Scholar 

  44. 44.

    Siu YT, Chin KT, Siu KL, Yee Wai CE, Jeang KT, Jin DY: TORC1 and TORC2 coactivators are required for tax activation of the human T-cell leukemia virus type 1 long terminal repeats. J Virol. 2006, 80: 7052-7059.

    PubMed Central  CAS  PubMed  Google Scholar 

  45. 45.

    Persengiev SP, Green MR: The role of ATF/CREB family members in cell growth, survival and apoptosis. Apoptosis. 2003, 8: 225-228.

    CAS  PubMed  Google Scholar 

  46. 46.

    Akagi T, Ono H, Nyunoya H, Shimotohno K: Characterization of peripheral blood T-lymphocytes transduced with HTLV-I Tax mutants with different trans-activating phenotypes. Oncogene. 1997, 14: 2071-2078.

    CAS  PubMed  Google Scholar 

  47. 47.

    Robek MD, Ratner L: Immortalization of CD4(+) and CD8(+) T lymphocytes by human T-cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone. J Virol. 1999, 73: 4856-4865.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. 48.

    Rosin O, Koch C, Schmitt I, Semmes OJ, Jeang KT, Grassmann R: A human T-cell leukemia virus Tax variant incapable of activating NF-kappaB retains its immortalizing potential for primary T-lymphocytes. J Biol Chem. 1998, 273: 6698-6703.

    CAS  PubMed  Google Scholar 

  49. 49.

    Matsumoto K, Shibata H, Fujisawa JI, Inoue H, Hakura A, Tsukahara T, Fujii M: Human T-cell leukemia virus type 1 Tax protein transforms rat fibroblasts via two distinct pathways. J Virol. 1997, 71: 4445-4451.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. 50.

    de la Fuente C, Gupta MV, Klase Z, Strouss K, Cahan P, McCaffery T, Galante A, Soteropoulos P, Pumfery A, Fujii M, Kashanchi F: Involvement of HTLV-I Tax and CREB in aneuploidy: a bioinformatics approach. Retrovirology. 2006, 3: 43-

    PubMed Central  PubMed  Google Scholar 

  51. 51.

    Dodon MD, Li Z, Hamaia S, Gazzolo L: Tax protein of human T-cell leukaemia virus type 1 induces interleukin 17 gene expression in T cells. J Gen Virol. 2004, 85: 1921-1932.

    PubMed  Google Scholar 

  52. 52.

    Alexandre C, Verrier B: Four regulatory elements in the human c-fos promoter mediate transactivation by HTLV-1 Tax protein. Oncogene. 1991, 6: 543-551.

    CAS  PubMed  Google Scholar 

  53. 53.

    Kibler KV, Jeang KT: CREB/ATF-dependent repression of cyclin a by human T-cell leukemia virus type 1 Tax protein. J Virol. 2001, 75: 2161-2173.

    PubMed Central  CAS  PubMed  Google Scholar 

  54. 54.

    Mulloy JC, Kislyakova T, Cereseto A, Casareto L, LoMonico A, Fullen J, Lorenzi MV, Cara A, Nicot C, Giam C, Franchini G: Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell cycle arrest and apoptosis through its CREB/ATF functional domain. J Virol. 1998, 72: 8852-8860.

    PubMed Central  CAS  PubMed  Google Scholar 

  55. 55.

    Nicot C, Opavsky R, Mahieux R, Johnson JM, Brady JN, Wolff L, Franchini G: Tax oncoprotein trans-represses endogenous B-myb promoter activity in human T cells. AIDS Res Hum Retroviruses. 2000, 16: 1629-1632.

    CAS  PubMed  Google Scholar 

  56. 56.

    Fujii M, Niki T, Mori T, Matsuda T, Matsui M, Nomura N, Seiki M: HTLV-1 Tax induces expression of various immediate early serum responsive genes. Oncogene. 1991, 6: 1023-1029.

    CAS  PubMed  Google Scholar 

  57. 57.

    Fujii M, Iwai K, Oie M, Fukushi M, Yamamoto N, Kannagi M, Mori N: Activation of oncogenic transcription factor AP-1 in T cells infected with human T cell leukemia virus type 1. AIDS Res Hum Retroviruses. 2000, 16: 1603-1606.

    CAS  PubMed  Google Scholar 

  58. 58.

    Alexandre C, Charnay P, Verrier B: Transactivation of Krox-20 and Krox-24 promoters by the HTLV-1 Tax protein through common regulatory elements. Oncogene. 1991, 6: 1851-1857.

    CAS  PubMed  Google Scholar 

  59. 59.

    Fujii M, Tsuchiya H, Chuhjo T, Akizawa T, Seiki M: Interaction of HTLV-1 Tax1 with p67SRF causes the aberrant induction of cellular immediate early genes through CArG boxes. Genes Dev. 1992, 6: 2066-2076.

    CAS  PubMed  Google Scholar 

  60. 60.

    Fujii M, Chuhjo T, Minamino T, Masaaki N, Miyamoto K, Seiki M: Identification of the Tax interaction region of serum response factor that mediates the aberrant induction of immediate early genes through CArG boxes by HTLV-I Tax. Oncogene. 1995, 11: 7-14.

    CAS  PubMed  Google Scholar 

  61. 61.

    Suzuki T, Hirai H, Fujisawa J, Fujita T, Yoshida M: A trans-activator Tax of human T-cell leukemia virus type 1 binds to NF-kappa B p50 and serum response factor (SRF) and associates with enhancer DNAs of the NF-kappa B site and CArG box. Oncogene. 1993, 8: 2391-2397.

    CAS  PubMed  Google Scholar 

  62. 62.

    Dittmer J, Pise-Masison CA, Clemens KE, Choi KS, Brady JN: Interaction of human T-cell lymphotropic virus type I Tax, Ets1, and Sp1 in transactivation of the PTHrP P2 promoter. J Biol Chem. 1997, 272: 4953-4958.

    CAS  PubMed  Google Scholar 

  63. 63.

    Shuh M, Derse D: Ternary complex factors and cofactors are essential for human T-cell leukemia virus type 1 tax transactivation of the serum response element. J Virol. 2000, 74: 11394-11397.

    PubMed Central  CAS  PubMed  Google Scholar 

  64. 64.

    Winter HY, Marriott SJ: Human T-cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J Virol. 2007, 81: 6089-6098.

    PubMed Central  CAS  PubMed  Google Scholar 

  65. 65.

    Inoue J, Seiki M, Taniguchi T, Tsuru S, Yoshida M: Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO J. 1986, 5: 2883-2888.

    PubMed Central  CAS  PubMed  Google Scholar 

  66. 66.

    Cross SL, Feinberg MB, Wolf JB, Holbrook NJ, Wong-Staal F, Leonard WJ: Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell. 1987, 49: 47-56.

    CAS  PubMed  Google Scholar 

  67. 67.

    Maruyama M, Shibuya H, Harada H, Hatakeyama M, Seiki M, Fujita T, Inoue J, Yoshida M, Taniguchi T: Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Cell. 1987, 48: 343-350.

    CAS  PubMed  Google Scholar 

  68. 68.

    Siekevitz M, Feinberg MB, Holbrook N, Wong-Staal F, Greene WC: Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A. 1987, 84: 5389-5393.

    PubMed Central  CAS  PubMed  Google Scholar 

  69. 69.

    Ballard DW, Bohnlein E, Lowenthal JW, Wano Y, Franza BR, Greene WC: HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science. 1988, 241: 1652-1655.

    CAS  PubMed  Google Scholar 

  70. 70.

    Crenon I, Beraud C, Simard P, Montagne J, Veschambre P, Jalinot P: The transcriptionally active factors mediating the effect of the HTLV-I Tax transactivator on the IL-2R alpha kappa B enhancer include the product of the c-rel proto-oncogene. Oncogene. 1993, 8: 867-875.

    CAS  PubMed  Google Scholar 

  71. 71.

    Siebenlist U, Franzoso G, Brown K: Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994, 10: 405-455.

    CAS  PubMed  Google Scholar 

  72. 72.

    Perkins ND: Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol. 2007, 8: 49-62.

    CAS  PubMed  Google Scholar 

  73. 73.

    Karin M, Ben Neriah Y: Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000, 18: 621-663.

    CAS  PubMed  Google Scholar 

  74. 74.

    Murakami T, Hirai H, Suzuki T, Fujisawa J, Yoshida M: HTLV-1 Tax enhances NF-kappa B2 expression and binds to the products p52 and p100, but does not suppress the inhibitory function of p100. Virology. 1995, 206: 1066-1074.

    CAS  PubMed  Google Scholar 

  75. 75.

    Suzuki T, Hirai H, Yoshida M: Tax protein of HTLV-1 interacts with the Rel homology domain of NF-kappa B p65 and c-Rel proteins bound to the NF-kappa B binding site and activates transcription. Oncogene. 1994, 9: 3099-3105.

    CAS  PubMed  Google Scholar 

  76. 76.

    Lamsoul I, Lodewick J, Lebrun S, Brasseur R, Burny A, Gaynor RB, Bex F: Exclusive ubiquitination and sumoylation on overlapping lysine residues mediate NF-kappaB activation by the human T-cell leukemia virus tax oncoprotein. Mol Cell Biol. 2005, 25: 10391-10406.

    PubMed Central  CAS  PubMed  Google Scholar 

  77. 77.

    Azran I, Jeang KT, Aboud M: High levels of cytoplasmic HTLV-1 Tax mutant proteins retain a Tax-NF-kappaB-CBP ternary complex in the cytoplasm. Oncogene. 2005, 24: 4521-4530.

    CAS  PubMed  Google Scholar 

  78. 78.

    Petropoulos L, Lin R, Hiscott J: Human T cell leukemia virus type 1 tax protein increases NF-kappa B dimer formation and antagonizes the inhibitory activity of the I kappa B alpha regulatory protein. Virology. 1996, 225: 52-64.

    CAS  PubMed  Google Scholar 

  79. 79.

    Bex F, Yin MJ, Burny A, Gaynor RB: Differential transcriptional activation by human T-cell leukemia virus type 1 Tax mutants is mediated by distinct interactions with CREB binding protein and p300. Mol Cell Biol. 1998, 18: 2392-2405.

    PubMed Central  CAS  PubMed  Google Scholar 

  80. 80.

    Bex F, Gaynor RB: Regulation of gene expression by HTLV-I Tax protein. Methods. 1998, 16: 83-94.

    CAS  PubMed  Google Scholar 

  81. 81.

    Tsukada J, Misago M, Serino Y, Ogawa R, Murakami S, Nakanishi M, Tonai S, Kominato Y, Morimoto I, Auron PE, Eto S: Human T-cell leukemia virus type I Tax transactivates the promoter of human prointerleukin-1beta gene through association with two transcription factors, nuclear factor-interleukin-6 and Spi-1. Blood. 1997, 90: 3142-3153.

    CAS  PubMed  Google Scholar 

  82. 82.

    Pise-Masison CA, Dittmer J, Clemens KE, Brady JN: Physical and functional interaction between the human T-cell lymphotropic virus type 1 Tax1 protein and the CCAAT binding protein NF-Y. Mol Cell Biol. 1997, 17: 1236-1243.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. 83.

    Hivin P, Gaudray G, Devaux C, Mesnard JM: Interaction between C/EBPbeta and Tax down-regulates human T-cell leukemia virus type I transcription. Virology. 2004, 318: 556-565.

    CAS  PubMed  Google Scholar 

  84. 84.

    Nerlov C: The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends Cell Biol. 2007, 17: 318-324.

    CAS  PubMed  Google Scholar 

  85. 85.

    Trejo SR, Fahl WE, Ratner L: The tax protein of human T-cell leukemia virus type 1 mediates the transactivation of the c-sis/platelet-derived growth factor-B promoter through interactions with the zinc finger transcription factors Sp1 and NGFI-A/Egr-1. J Biol Chem. 1997, 272: 27411-27421.

    CAS  PubMed  Google Scholar 

  86. 86.

    Richard V, Lairmore MD, Green PL, Feuer G, Erbe RS, Albrecht B, D'Souza C, Keller ET, Dai J, Rosol TJ: Humoral hypercalcemia of malignancy: severe combined immunodeficient/beige mouse model of adult T-cell lymphoma independent of human T-cell lymphotropic virus type-1 tax expression. Am J Pathol. 2001, 158: 2219-2228.

    PubMed Central  CAS  PubMed  Google Scholar 

  87. 87.

    Nadella MV, Shu ST, Dirksen WP, Thudi NK, Nadella KS, Fernandez SA, Lairmore MD, Green PL, Rosol TJ: Expression of parathyroid hormone-related protein during immortalization of human peripheral blood mononuclear cells by HTLV-1: implications for transformation. Retrovirology. 2008, 5: 46-

    PubMed Central  PubMed  Google Scholar 

  88. 88.

    Moriuchi M, Moriuchi H, Fauci AS: HTLV type I Tax activation of the CXCR4 promoter by association with nuclear respiratory factor 1. AIDS Res Hum Retroviruses. 1999, 15: 821-827.

    CAS  PubMed  Google Scholar 

  89. 89.

    Twizere JC, Lefebvre L, Collete D, Debacq C, Urbain P, Heremans H, Jauniaux JC, Burny A, Willems L, Kettmann R: The homeobox protein MSX2 interacts with tax oncoproteins and represses their transactivation activity. J Biol Chem. 2005, 280: 29804-29811.

    CAS  PubMed  Google Scholar 

  90. 90.

    Caron C, Rousset R, Beraud C, Moncollin V, Egly JM, Jalinot P: Functional and biochemical interaction of the HTLV-I Tax1 transactivator with TBP. EMBO J. 1993, 12: 4269-4278.

    PubMed Central  CAS  PubMed  Google Scholar 

  91. 91.

    Caron C, Mengus G, Dubrowskaya V, Roisin A, Davidson I, Jalinot P: Human TAF(II)28 interacts with the human T cell leukemia virus type I Tax transactivator and promotes its transcriptional activity. Proc Natl Acad Sci U S A. 1997, 94: 3662-3667.

    PubMed Central  CAS  PubMed  Google Scholar 

  92. 92.

    Clemens KE, Piras G, Radonovich MF, Choi KS, Duvall JF, DeJong J, Roeder R, Brady JN: Interaction of the human T-cell lymphotropic virus type 1 tax transactivator with transcription factor IIA. Mol Cell Biol. 1996, 16: 4656-4664.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. 93.

    Ching YP, Chun AC, Chin KT, Zhang ZQ, Jeang KT, Jin DY: Specific TATAA and bZIP requirements suggest that HTLV-I Tax has transcriptional activity subsequent to the assembly of an initiation complex. Retrovirology. 2004, 1: 18-

    PubMed Central  PubMed  Google Scholar 

  94. 94.

    Peterson CL: Chromatin remodeling enzymes: taming the machines. Third in review series on chromatin dynamics. EMBO Rep. 2002, 3: 319-322.

    PubMed Central  CAS  PubMed  Google Scholar 

  95. 95.

    Peterson CL: Chromatin remodeling: nucleosomes bulging at the seams. Curr Biol. 2002, 12: R245-R247.

    CAS  PubMed  Google Scholar 

  96. 96.

    Ruthenburg AJ, Li H, Patel DJ, Allis CD: Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol. 2007, 8: 983-994.

    CAS  PubMed  Google Scholar 

  97. 97.

    Bogenberger JM, Laybourn PJ: Human T Lymphotropic Virus Type 1 protein Tax reduces histone levels. Retrovirology. 2008, 5: 9-

    PubMed Central  PubMed  Google Scholar 

  98. 98.

    Giebler HA, Loring JE, van Orden K, Colgin MA, Garrus JE, Escudero KW, Brauweiler A, Nyborg JK: Anchoring of CREB binding protein to the human T-cell leukemia virus type 1 promoter: a molecular mechanism of Tax transactivation. Mol Cell Biol. 1997, 17: 5156-5164.

    PubMed Central  CAS  PubMed  Google Scholar 

  99. 99.

    Lenzmeier BA, Giebler HA, Nyborg JK: Human T-cell leukemia virus type 1 Tax requires direct access to DNA for recruitment of CREB binding protein to the viral promoter. Mol Cell Biol. 1998, 18: 721-731.

    PubMed Central  CAS  PubMed  Google Scholar 

  100. 100.

    Kwok RP, Laurance ME, Lundblad JR, Goldman PS, Shih H, Connor LM, Marriott SJ, Goodman RH: Control of cAMP-regulated enhancers by the viral transactivator Tax through CREB and the co-activator CBP. Nature. 1996, 380: 642-646.

    CAS  PubMed  Google Scholar 

  101. 101.

    Jiang H, Lu H, Schiltz RL, Pise-Masison CA, Ogryzko VV, Nakatani Y, Brady JN: PCAF interacts with tax and stimulates tax transactivation in a histone acetyltransferase-independent manner. Mol Cell Biol. 1999, 19: 8136-8145.

    PubMed Central  CAS  PubMed  Google Scholar 

  102. 102.

    Harrod R, Kuo YL, Tang Y, Yao Y, Vassilev A, Nakatani Y, Giam CZ: p300 and p300/cAMP-responsive element-binding protein associated factor interact with human T-cell lymphotropic virus type-1 Tax in a multi-histone acetyltransferase/activator-enhancer complex. J Biol Chem. 2000, 275: 11852-11857.

    CAS  PubMed  Google Scholar 

  103. 103.

    Okada M, Jeang KT: Differential requirements for activation of integrated and transiently transfected human T-cell leukemia virus type 1 long terminal repeat. J Virol. 2002, 76: 12564-12573.

    PubMed Central  CAS  PubMed  Google Scholar 

  104. 104.

    Georges SA, Kraus WL, Luger K, Nyborg JK, Laybourn PJ: p300-mediated tax transactivation from recombinant chromatin: histone tail deletion mimics coactivator function. Mol Cell Biol. 2002, 22: 127-137.

    PubMed Central  CAS  PubMed  Google Scholar 

  105. 105.

    Lu H, Pise-Masison CA, Fletcher TM, Schiltz RL, Nagaich AK, Radonovich M, Hager G, Cole PA, Brady JN: Acetylation of nucleosomal histones by p300 facilitates transcription from tax-responsive human T-cell leukemia virus type 1 chromatin template. Mol Cell Biol. 2002, 22: 4450-4462.

    PubMed Central  CAS  PubMed  Google Scholar 

  106. 106.

    Parker D, Ferreri K, Nakajima T, LaMorte VJ, Evans R, Koerber SC, Hoeger C, Montminy MR: Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism. Mol Cell Biol. 1996, 16: 694-703.

    PubMed Central  CAS  PubMed  Google Scholar 

  107. 107.

    Radhakrishnan I, Perez-Alvarado GC, Parker D, Dyson HJ, Montminy MR, Wright PE: Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions. Cell. 1997, 91: 741-752.

    CAS  PubMed  Google Scholar 

  108. 108.

    Johannessen M, Delghandi MP, Moens U: What turns CREB on?. Cell Signal. 2004, 16: 1211-1227.

    CAS  PubMed  Google Scholar 

  109. 109.

    Trevisan R, Daprai L, Acquasaliente L, Ciminale V, Chieco-Bianchi L, Saggioro D: Relevance of CREB phosphorylation in the anti-apoptotic function of human T-lymphotropic virus type 1 tax protein in serum-deprived murine fibroblasts. Exp Cell Res. 2004, 299: 57-67.

    CAS  PubMed  Google Scholar 

  110. 110.

    Kim YM, Ramirez JA, Mick JE, Giebler HA, Yan JP, Nyborg JK: Molecular characterization of the Tax-containing HTLV-1 enhancer complex reveals a prominent role for CREB phosphorylation in Tax transactivation. J Biol Chem. 2007, 282: 18750-18757.

    CAS  PubMed  Google Scholar 

  111. 111.

    Ramirez JA, Nyborg JK: Molecular characterization of HTLV-1 Tax interaction with the KIX domain of CBP/p300. J Mol Biol. 2007, 372: 958-969.

    PubMed Central  CAS  PubMed  Google Scholar 

  112. 112.

    Geiger TR, Sharma N, Kim YM, Nyborg JK: The human T-cell leukemia virus type 1 tax protein confers CBP/p300 recruitment and transcriptional activation properties to phosphorylated CREB. Mol Cell Biol. 2008, 28: 1383-1392.

    PubMed Central  CAS  PubMed  Google Scholar 

  113. 113.

    Livengood JA, Scoggin KE, van Orden K, McBryant SJ, Edayathumangalam RS, Laybourn PJ, Nyborg JK: p53 Transcriptional activity is mediated through the SRC1-interacting domain of CBP/p300. J Biol Chem. 2002, 277: 9054-9061.

    CAS  PubMed  Google Scholar 

  114. 114.

    Riou P, Bex F, Gazzolo L: The human T cell leukemia/lymphotropic virus type 1 Tax protein represses MyoD-dependent transcription by inhibiting MyoD-binding to the KIX domain of p300. A potential mechanism for Tax-mediated repression of the transcriptional activity of basic helix-loop-helix factors. J Biol Chem. 2000, 275: 10551-10560.

    CAS  PubMed  Google Scholar 

  115. 115.

    Yoshida M: Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol. 2001, 19: 475-496.

    CAS  PubMed  Google Scholar 

  116. 116.

    Zhang J, Yamada O, Kawagishi K, Araki H, Yamaoka S, Hattori T, Shimotohno K: Human T-cell leukemia virus type 1 Tax modulates interferon-alpha signal transduction through competitive usage of the coactivator CBP/p300. Virology. 2008, Epub ahead of print

  117. 117.

    Tabakin-Fix Y, Azran I, Schavinky-Khrapunsky Y, Levy O, Aboud M: Functional inactivation of p53 by human T-cell leukemia virus type 1 Tax protein: mechanisms and clinical implications. Carcinogenesis. 2006, 27: 673-681.

    CAS  PubMed  Google Scholar 

  118. 118.

    Lemasson I, Polakowski NJ, Laybourn PJ, Nyborg JK: Transcription regulatory complexes bind the human T-cell leukemia virus 5' and 3' long terminal repeats to control gene expression. Mol Cell Biol. 2004, 24: 6117-6126.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. 119.

    Ego T, Ariumi Y, Shimotohno K: The interaction of HTLV-1 Tax with HDAC1 negatively regulates the viral gene expression. Oncogene. 2002, 21: 7241-7246.

    CAS  PubMed  Google Scholar 

  120. 120.

    Lu H, Pise-Masison CA, Linton R, Park HU, Schiltz RL, Sartorelli V, Brady JN: Tax relieves transcriptional repression by promoting histone deacetylase 1 release from the human T-cell leukemia virus type 1 long terminal repeat. J Virol. 2004, 78: 6735-6743.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. 121.

    Cheng J, Kydd AR, Nakase K, Noonan KM, Murakami A, Tao H, Dwyer M, Xu C, Zhu Q, Marasco WA: Negative regulation of the SH2-homology containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein. Blood. 2007, 110: 2110-2120.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. 122.

    Ariumi Y, Ego T, Kaida A, Matsumoto M, Pandolfi PP, Shimotohno K: Distinct nuclear body components, PML and SMRT, regulate the trans-acting function of HTLV-1 Tax oncoprotein. Oncogene. 2003, 22: 1611-1619.

    CAS  PubMed  Google Scholar 

  123. 123.

    Ego T, Tanaka Y, Shimotohno K: Interaction of HTLV-1 Tax and methyl-CpG-binding domain 2 positively regulates the gene expression from the hypermethylated LTR. Oncogene. 2005, 24: 1914-1923.

    CAS  PubMed  Google Scholar 

  124. 124.

    Kamoi K, Yamamoto K, Misawa A, Miyake A, Ishida T, Tanaka Y, Mochizuki M, Watanabe T: SUV39H1 interacts with HTLV-1 Tax and abrogates Tax transactivation of HTLV-1 LTR. Retrovirology. 2006, 3: 5-

    PubMed Central  PubMed  Google Scholar 

  125. 125.

    Gray SG, Iglesias AH, Lizcano F, Villanueva R, Camelo S, Jingu H, Teh BT, Koibuchi N, Chin WW, Kokkotou E, Dangond F: Functional characterization of JMJD2A, a histone deacetylase- and retinoblastoma-binding protein. J Biol Chem. 2005, 280: 28507-28518.

    CAS  PubMed  Google Scholar 

  126. 126.

    Kouzarides T: Chromatin modifications and their function. Cell. 2007, 128: 693-705.

    CAS  PubMed  Google Scholar 

  127. 127.

    Jeong SJ, Lu H, Cho WK, Park HU, Pise-Masison C, Brady JN: Coactivator-associated arginine methyltransferase 1 enhances transcriptional activity of the human T-cell lymphotropic virus type 1 long terminal repeat through direct interaction with Tax. J Virol. 2006, 80: 10036-10044.

    PubMed Central  CAS  PubMed  Google Scholar 

  128. 128.

    Li B, Carey M, Workman JL: The role of chromatin during transcription. Cell. 2007, 128: 707-719.

    CAS  PubMed  Google Scholar 

  129. 129.

    Wang W: The SWI/SNF family of ATP-dependent chromatin remodelers: similar mechanisms for diverse functions. Curr Top Microbiol Immunol. 2003, 274: 143-169.

    CAS  PubMed  Google Scholar 

  130. 130.

    Wu K, Bottazzi ME, de la FC, Deng L, Gitlin SD, Maddukuri A, Dadgar S, Li H, Vertes A, Pumfery A, Kashanchi F: Protein profile of tax-associated complexes. J Biol Chem. 2004, 279: 495-508.

    CAS  PubMed  Google Scholar 

  131. 131.

    Zhang L, Liu M, Merling R, Giam CZ: Versatile reporter systems show that transactivation by human T-cell leukemia virus type 1 Tax occurs independently of chromatin remodeling factor BRG1. J Virol. 2006, 80: 7459-7468.

    PubMed Central  CAS  PubMed  Google Scholar 

  132. 132.

    Lemasson I, Polakowski NJ, Laybourn PJ, Nyborg JK: Tax-dependent displacement of nucleosomes during transcriptional activation of human T-cell leukemia virus type 1. J Biol Chem. 2006, 281: 13075-13082.

    CAS  PubMed  Google Scholar 

  133. 133.

    Workman JL: Nucleosome displacement in transcription. Genes Dev. 2006, 20: 2009-2017.

    CAS  PubMed  Google Scholar 

  134. 134.

    Gavin I, Horn PJ, Peterson CL: SWI/SNF chromatin remodeling requires changes in DNA topology. Mol Cell. 2001, 7: 97-104.

    CAS  PubMed  Google Scholar 

  135. 135.

    Suzuki T, Uchida-Toita M, Andoh T, Yoshida M: HTLV-1 tax oncoprotein binds to DNA topoisomerase I and inhibits its catalytic activity. Virology. 2000, 270: 291-298.

    CAS  PubMed  Google Scholar 

  136. 136.

    Peterlin BM, Price DH: Controlling the elongation phase of transcription with P-TEFb. Mol Cell. 2006, 23: 297-305.

    CAS  PubMed  Google Scholar 

  137. 137.

    Price DH: P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol. 2000, 20: 2629-2634.

    PubMed Central  CAS  PubMed  Google Scholar 

  138. 138.

    Cho WK, Zhou M, Jang MK, Huang K, Jeong SJ, Ozato K, Brady JN: Modulation of the Brd4/P-TEFb interaction by the human T-lymphotropic virus type 1 tax protein. J Virol. 2007, 81: 11179-11186.

    PubMed Central  CAS  PubMed  Google Scholar 

  139. 139.

    Zhou M, Lu H, Park H, Wilson-Chiru J, Linton R, Brady JN: Tax interacts with P-TEFb in a novel manner to stimulate human T-lymphotropic virus type 1 transcription. J Virol. 2006, 80: 4781-4791.

    PubMed Central  CAS  PubMed  Google Scholar 

  140. 140.

    Lin S, Coutinho-Mansfield G, Wang D, Pandit S, Fu XD: The splicing factor SC35 has an active role in transcriptional elongation. Nat Struct Mol Biol. 2008, 15: 819-826.

    PubMed Central  CAS  PubMed  Google Scholar 

  141. 141.

    Semmes OJ, Jeang KT: Localization of human T-cell leukemia virus type 1 tax to subnuclear compartments that overlap with interchromatin speckles. J Virol. 1996, 70: 6347-6357.

    PubMed Central  CAS  PubMed  Google Scholar 

  142. 142.

    Gronemeyer H, Gustafsson JA, Laudet V: Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov. 2004, 3: 950-964.

    CAS  PubMed  Google Scholar 

  143. 143.

    Doucas V, Evans RM: Human T-cell leukemia retrovirus-Tax protein is a repressor of nuclear receptor signaling. Proc Natl Acad Sci U S A. 1999, 96: 2633-2638.

    PubMed Central  CAS  PubMed  Google Scholar 

  144. 144.

    Chin KT, Chun AC, Ching YP, Jeang KT, Jin DY: Human T-cell leukemia virus oncoprotein tax represses nuclear receptor-dependent transcription by targeting coactivator TAX1BP1. Cancer Res. 2007, 67: 1072-1081.

    CAS  PubMed  Google Scholar 

  145. 145.

    Blackshear PJ: Tristetraprolin and other CCCH tandem zinc-finger proteins in the regulation of mRNA turnover. Biochem Soc Trans. 2002, 30: 945-952.

    CAS  PubMed  Google Scholar 

  146. 146.

    Anderson P, Kedersha N: RNA granules. J Cell Biol. 2006, 172: 803-808.

    PubMed Central  CAS  PubMed  Google Scholar 

  147. 147.

    Bakheet T, Williams BR, Khabar KS: ARED 3.0: the large and diverse AU-rich transcriptome. Nucleic Acids Res. 2006, 34: D111-D114.

    PubMed Central  CAS  PubMed  Google Scholar 

  148. 148.

    Twizere JC, Kruys V, Lefebvre L, Vanderplasschen A, Collete D, Debacq C, Lai WS, Jauniaux JC, Bernstein LR, Semmes OJ, Burny A, Blackshear PJ, Kettmann R, Willems L: Interaction of retroviral Tax oncoproteins with tristetraprolin and regulation of tumor necrosis factor-alpha expression. J Natl Cancer Inst. 2003, 95: 1846-1859.

    CAS  PubMed  Google Scholar 

  149. 149.

    Desbois C, Rousset R, Bantignies F, Jalinot P: Exclusion of Int-6 from PML nuclear bodies by binding to the HTLV-I Tax oncoprotein. Science. 1996, 273: 951-953.

    CAS  PubMed  Google Scholar 

  150. 150.

    Donzeau M, Winnacker EL, Meisterernst M: Specific repression of Tax trans-activation by TAR RNA-binding protein TRBP. J Virol. 1997, 71: 2628-2635.

    PubMed Central  CAS  PubMed  Google Scholar 

  151. 151.

    Dejardin E: The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol. 2006, 72: 1161-1179.

    CAS  PubMed  Google Scholar 

  152. 152.

    Higuchi M, Tsubata C, Kondo R, Yoshida S, Takahashi M, Oie M, Tanaka Y, Mahieux R, Matsuoka M, Fujii M: Cooperation of NF-kappaB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line. J Virol. 2007, 81: 11900-11907.

    PubMed Central  CAS  PubMed  Google Scholar 

  153. 153.

    Sun SC, Yamaoka S: Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene. 2005, 24: 5952-5964.

    CAS  PubMed  Google Scholar 

  154. 154.

    Xiao G, Cvijic ME, Fong A, Harhaj EW, Uhlik MT, Waterfield M, Sun SC: Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: evidence for the involvement of IKKalpha. EMBO J. 2001, 20: 6805-6815.

    PubMed Central  CAS  PubMed  Google Scholar 

  155. 155.

    Harhaj EW, Sun SC: IKKgamma serves as a docking subunit of the IkappaB kinase (IKK) and mediates interaction of IKK with the human T-cell leukemia virus Tax protein. J Biol Chem. 1999, 274: 22911-22914.

    CAS  PubMed  Google Scholar 

  156. 156.

    Jin DY, Giordano V, Kibler KV, Nakano H, Jeang KT: Role of adapter function in oncoprotein-mediated activation of NF-kappaB. Human T-cell leukemia virus type I Tax interacts directly with IkappaB kinase gamma. J Biol Chem. 1999, 274: 17402-17405.

    CAS  PubMed  Google Scholar 

  157. 157.

    Yin MJ, Christerson LB, Yamamoto Y, Kwak YT, Xu S, Mercurio F, Barbosa M, Cobb MH, Gaynor RB: HTLV-I Tax protein binds to MEKK1 to stimulate IkappaB kinase activity and NF-kappaB activation. Cell. 1998, 93: 875-884.

    CAS  PubMed  Google Scholar 

  158. 158.

    Wu X, Sun SC: Retroviral oncoprotein Tax deregulates NF-kappaB by activating Tak1 and mediating the physical association of Tak1-IKK. EMBO Rep. 2007, 8: 510-515.

    PubMed Central  CAS  PubMed  Google Scholar 

  159. 159.

    Chu ZL, DiDonato JA, Hawiger J, Ballard DW: The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IkappaB kinases containing IKKalpha and IKKbeta. J Biol Chem. 1998, 273: 15891-15894.

    CAS  PubMed  Google Scholar 

  160. 160.

    Gohda J, Irisawa M, Tanaka Y, Sato S, Ohtani K, Fujisawa J, Inoue J: HTLV-1 Tax-induced NFkappaB activation is independent of Lys-63-linked-type polyubiquitination. Biochem Biophys Res Commun. 2007, 357: 225-230.

    CAS  PubMed  Google Scholar 

  161. 161.

    Hirai H, Suzuki T, Fujisawa J, Inoue J, Yoshida M: Tax protein of human T-cell leukemia virus type I binds to the ankyrin motifs of inhibitory factor kappa B and induces nuclear translocation of transcription factor NF-kappa B proteins for transcriptional activation. Proc Natl Acad Sci U S A. 1994, 91: 3584-3588.

    PubMed Central  CAS  PubMed  Google Scholar 

  162. 162.

    Suzuki T, Hirai H, Murakami T, Yoshida M: Tax protein of HTLV-1 destabilizes the complexes of NF-kappa B and I kappa B-alpha and induces nuclear translocation of NF-kappa B for transcriptional activation. Oncogene. 1995, 10: 1199-1207.

    CAS  PubMed  Google Scholar 

  163. 163.

    Rousset R, Desbois C, Bantignies F, Jalinot P: Effects on NF-kappa B1/p105 processing of the interaction between the HTLV-1 transactivator Tax and the proteasome. Nature. 1996, 381: 328-331.

    CAS  PubMed  Google Scholar 

  164. 164.

    Chen ZJ: Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol. 2005, 7: 758-765.

    PubMed Central  CAS  PubMed  Google Scholar 

  165. 165.

    Perkins ND: Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene. 2006, 25: 6717-6730.

    CAS  PubMed  Google Scholar 

  166. 166.

    Kray AE, Carter RS, Pennington KN, Gomez RJ, Sanders LE, Llanes JM, Khan WN, Ballard DW, Wadzinski BE: Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A. J Biol Chem. 2005, 280: 35974-35982.

    CAS  PubMed  Google Scholar 

  167. 167.

    Palkowitsch L, Leidner J, Ghosh S, Marienfeld RB: Phosphorylation of serine 68 in the IkappaB kinase (IKK)-binding domain of NEMO interferes with the structure of the IKK complex and tumor necrosis factor-alpha-induced NF-kappaB activity. J Biol Chem. 2008, 283: 76-86.

    CAS  PubMed  Google Scholar 

  168. 168.

    Fu DX, Kuo YL, Liu BY, Jeang KT, Giam CZ: Human T-lymphotropic virus type I tax activates I-kappa B kinase by inhibiting I-kappa B kinase-associated serine/threonine protein phosphatase 2A. J Biol Chem. 2003, 278: 1487-1493.

    CAS  PubMed  Google Scholar 

  169. 169.

    Hong S, Wang LC, Gao X, Kuo YL, Liu B, Merling R, Kung HJ, Shih HM, Giam CZ: Heptad repeats regulate protein phosphatase 2a recruitment to I-kappaB kinase gamma/NF-kappaB essential modulator and are targeted by human T-lymphotropic virus type 1 tax. J Biol Chem. 2007, 282: 12119-12126.

    CAS  PubMed  Google Scholar 

  170. 170.

    Shembade N, Harhaj NS, Yamamoto M, Akira S, Harhaj EW: The human T-cell leukemia virus type 1 Tax oncoprotein requires the ubiquitin-conjugating enzyme Ubc13 for NF-kappaB activation. J Virol. 2007, 81: 13735-13742.

    PubMed Central  CAS  PubMed  Google Scholar 

  171. 171.

    Shembade N, Harhaj NS, Parvatiyar K, Copeland NG, Jenkins NA, Matesic LE, Harhaj EW: The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. Nat Immunol. 2008, 9: 254-262.

    CAS  PubMed  Google Scholar 

  172. 172.

    Shembade N, Harhaj NS, Liebl DJ, Harhaj EW: Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling. EMBO J. 2007, 26: 3910-3922.

    PubMed Central  CAS  PubMed  Google Scholar 

  173. 173.

    Iha H, Peloponese JM, Verstrepen L, Zapart G, Ikeda F, Smith CD, Starost MF, Yedavalli V, Heyninck K, Dikic I, Beyaert R, Jeang KT: Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-kappaB activation. EMBO J. 2008, 27: 629-641.

    PubMed Central  CAS  PubMed  Google Scholar 

  174. 174.

    Heyninck K, Beyaert R: A20 inhibits NF-kappaB activation by dual ubiquitin-editing functions. Trends Biochem Sci. 2005, 30: 1-4.

    CAS  PubMed  Google Scholar 

  175. 175.

    Pimienta G, Pascual J: Canonical and alternative MAPK signaling. Cell Cycle. 2007, 6: 2628-2632.

    CAS  PubMed  Google Scholar 

  176. 176.

    Yujiri T, Sather S, Fanger GR, Johnson GL: Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science. 1998, 282: 1911-1914.

    CAS  PubMed  Google Scholar 

  177. 177.

    Yujiri T, Ware M, Widmann C, Oyer R, Russell D, Chan E, Zaitsu Y, Clarke P, Tyler K, Oka Y, Fanger GR, Henson P, Johnson GL: MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation. Proc Natl Acad Sci U S A. 2000, 97: 7272-7277.

    PubMed Central  CAS  PubMed  Google Scholar 

  178. 178.

    Delaney JR, Mlodzik M: TGF-beta activated kinase-1: new insights into the diverse roles of TAK1 in development and immunity. Cell Cycle. 2006, 5: 2852-2855.

    CAS  PubMed  Google Scholar 

  179. 179.

    Adhikari A, Xu M, Chen ZJ: Ubiquitin-mediated activation of TAK1 and IKK. Oncogene. 2007, 26: 3214-3226.

    CAS  PubMed  Google Scholar 

  180. 180.

    Suzuki S, Singhirunnusorn P, Mori A, Yamaoka S, Kitajima I, Saiki I, Sakurai H: Constitutive activation of TAK1 by HTLV-1 tax-dependent overexpression of TAB2 induces activation of JNK-ATF2 but not IKK-NF-kappaB. J Biol Chem. 2007, 282: 25177-25181.

    CAS  PubMed  Google Scholar 

  181. 181.

    Yu Q, Minoda Y, Yoshida R, Yoshida H, Iha H, Kobayashi T, Yoshimura A, Takaesu G: HTLV-1 Tax-mediated TAK1 activation involves TAB2 adapter protein. Biochem Biophys Res Commun. 2008, 365: 189-194.

    CAS  PubMed  Google Scholar 

  182. 182.

    Xu X, Heidenreich O, Kitajima I, McGuire K, Li Q, Su B, Nerenberg M: Constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis. Oncogene. 1996, 13: 135-142.

    CAS  PubMed  Google Scholar 

  183. 183.

    Jin DY, Teramoto H, Giam CZ, Chun RF, Gutkind JS, Jeang KT: A human suppressor of c-Jun N-terminal kinase 1 activation by tumor necrosis factor alpha. J Biol Chem. 1997, 272: 25816-25823.

    CAS  PubMed  Google Scholar 

  184. 184.

    Arnulf B, Villemain A, Nicot C, Mordelet E, Charneau P, Kersual J, Zermati Y, Mauviel A, Bazarbachi A, Hermine O: Human T-cell lymphotropic virus oncoprotein Tax represses TGF-beta 1 signaling in human T cells via c-Jun activation: a potential mechanism of HTLV-I leukemogenesis. Blood. 2002, 100: 4129-4138.

    CAS  PubMed  Google Scholar 

  185. 185.

    Kasai T, Jeang KT: Two discrete events, human T-cell leukemia virus type I Tax oncoprotein expression and a separate stress stimulus, are required for induction of apoptosis in T-cells. Retrovirology. 2004, 1: 7-

    PubMed Central  PubMed  Google Scholar 

  186. 186.

    Spain BH, Bowdish KS, Pacal AR, Staub SF, Koo D, Chang CY, Xie W, Colicelli J: Two human cDNAs, including a homolog of Arabidopsis FUS6 (COP11), suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction in yeast and mammalian cells. Mol Cell Biol. 1996, 16: 6698-6706.

    PubMed Central  CAS  PubMed  Google Scholar 

  187. 187.

    Zhang J, Kalkum M, Chait BT, Roeder RG: The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol Cell. 2002, 9: 611-623.

    CAS  PubMed  Google Scholar 

  188. 188.

    Jaffe AB, Hall A: Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol. 2005, 21: 247-269.

    CAS  PubMed  Google Scholar 

  189. 189.

    Reddy TR, Li X, Jones Y, Ellisman MH, Ching GY, Liem RK, Wong-Staal F: Specific interaction of HTLV tax protein and a human type IV neuronal intermediate filament protein. Proc Natl Acad Sci U S A. 1998, 95: 702-707.

    PubMed Central  CAS  PubMed  Google Scholar 

  190. 190.

    Trihn D, Jeang KT, Semmes OJ: HTLV-I Tax and Cytokeratin: Tax-Expressing Cells Show Morphological Changes in Keratin-Containing Cytoskeletal Networks. J Biomed Sci. 1997, 4: 47-53.

    CAS  PubMed  Google Scholar 

  191. 191.

    Kfoury Y, Nasr R, Favre-Bonvin A, El Sabban M, Renault N, Giron ML, Setterblad N, Hajj HE, Chiari E, Mikati AG, Hermine O, Saib A, de The H, Pique C, Bazarbachi A: Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome. Oncogene. 2008, 27: 1665-1676.

    CAS  PubMed  Google Scholar 

  192. 192.

    Nejmeddine M, Barnard AL, Tanaka Y, Taylor GP, Bangham CR: Human T-lymphotropic virus, type 1, tax protein triggers microtubule reorientation in the virological synapse. J Biol Chem. 2005, 280: 29653-29660.

    CAS  PubMed  Google Scholar 

  193. 193.

    Oldham WM, Hamm HE: Heterotrimeric G protein activation by G-protein-coupled receptors. Nat Rev Mol Cell Biol. 2008, 9: 60-71.

    CAS  PubMed  Google Scholar 

  194. 194.

    Ohshima K: Pathological features of diseases associated with human T-cell leukemia virus type I. Cancer Sci. 2007, 98: 772-778.

    CAS  PubMed  Google Scholar 

  195. 195.

    Fruman DA, Meyers RE, Cantley LC: Phosphoinositide kinases. Annu Rev Biochem. 1998, 67: 481-507.

    CAS  PubMed  Google Scholar 

  196. 196.

    Vanhaesebroeck B, Waterfield MD: Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999, 253: 239-254.

    CAS  PubMed  Google Scholar 

  197. 197.

    Zhang X, Jin B, Huang C: The PI3K/Akt pathway and its downstream transcriptional factors as targets for chemoprevention. Curr Cancer Drug Targets. 2007, 7: 305-316.

    CAS  PubMed  Google Scholar 

  198. 198.

    Liu Y, Wang Y, Yamakuchi M, Masuda S, Tokioka T, Yamaoka S, Maruyama I, Kitajima I: Phosphoinositide-3 kinase-PKB/Akt pathway activation is involved in fibroblast Rat-1 transformation by human T-cell leukemia virus type I tax. Oncogene. 2001, 20: 2514-2526.

    CAS  PubMed  Google Scholar 

  199. 199.

    Peloponese JM, Jeang KT: Role for Akt/protein kinase B and activator protein-1 in cellular proliferation induced by the human T-cell leukemia virus type 1 tax oncoprotein. J Biol Chem. 2006, 281: 8927-8938.

    CAS  PubMed  Google Scholar 

  200. 200.

    Paez J, Sellers WR: PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res. 2003, 115: 145-167.

    CAS  PubMed  Google Scholar 

  201. 201.

    Yu J, Wjasow C, Backer JM: Regulation of the p85/p110alpha phosphatidylinositol 3'-kinase. Distinct roles for the n-terminal and c-terminal SH2 domains. J Biol Chem. 1998, 273: 30199-30203.

    CAS  PubMed  Google Scholar 

  202. 202.

    Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM: Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol Cell Biol. 1998, 18: 1379-1387.

    PubMed Central  CAS  PubMed  Google Scholar 

  203. 203.

    Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC, Kahn CR: Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol. 2002, 22: 965-977.

    PubMed Central  CAS  PubMed  Google Scholar 

  204. 204.

    Mori N, Fujii M, Iwai K, Ikeda S, Yamasaki Y, Hata T, Yamada Y, Tanaka Y, Tomonaga M, Yamamoto N: Constitutive activation of transcription factor AP-1 in primary adult T-cell leukemia cells. Blood. 2000, 95: 3915-3921.

    CAS  PubMed  Google Scholar 

  205. 205.

    Iwai K, Mori N, Oie M, Yamamoto N, Fujii M: Human T-cell leukemia virus type 1 tax protein activates transcription through AP-1 site by inducing DNA binding activity in T cells. Virology. 2001, 279: 38-46.

    CAS  PubMed  Google Scholar 

  206. 206.

    Pennison M, Pasche B: Targeting transforming growth factor-beta signaling. Curr Opin Oncol. 2007, 19: 579-585.

    PubMed Central  CAS  PubMed  Google Scholar 

  207. 207.

    Schmierer B, Hill CS: TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007, 8: 970-982.

    CAS  PubMed  Google Scholar 

  208. 208.

    Kim SJ, Kehrl JH, Burton J, Tendler CL, Jeang KT, Danielpour D, Thevenin C, Kim KY, Sporn MB, Roberts AB: Transactivation of the transforming growth factor beta 1 (TGF-beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-beta 1 in adult T cell leukemia. J Exp Med. 1990, 172: 121-129.

    CAS  PubMed  Google Scholar 

  209. 209.

    Nagai M, Ijichi S, Hall WW, Osame M: Differential effect of TGF-beta 1 on the in vitro activation of HTLV-I and the proliferative response of CD8+ T lymphocytes in patients with HTLV-I-associated myelopathy (HAM/TSP). Clin Immunol Immunopathol. 1995, 77: 324-331.

    CAS  PubMed  Google Scholar 

  210. 210.

    Moriuchi M, Moriuchi H: Transforming growth factor-beta enhances human T-cell leukemia virus type I infection. J Med Virol. 2002, 67: 427-430.

    CAS  PubMed  Google Scholar 

  211. 211.

    Jones KS, Akel S, Petrow-Sadowski C, Huang Y, Bertolette DC, Ruscetti FW: Induction of human T cell leukemia virus type I receptors on quiescent naive T lymphocytes by TGF-beta. J Immunol. 2005, 174: 4262-4270.

    CAS  PubMed  Google Scholar 

  212. 212.

    Lee DK, Kim BC, Brady JN, Jeang KT, Kim SJ: Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-beta signaling by blocking the association of Smad proteins with Smad-binding element. J Biol Chem. 2002, 277: 33766-33775.

    CAS  PubMed  Google Scholar 

  213. 213.

    Mori N, Morishita M, Tsukazaki T, Giam CZ, Kumatori A, Tanaka Y, Yamamoto N: Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300. Blood. 2001, 97: 2137-2144.

    CAS  PubMed  Google Scholar 

  214. 214.

    Defilippi P, Di Stefano P, Cabodi S: p130Cas: a versatile scaffold in signaling networks. Trends Cell Biol. 2006, 16: 257-263.

    CAS  PubMed  Google Scholar 

  215. 215.

    Iwata S, Souta-Kuribara A, Yamakawa A, Sasaki T, Shimizu T, Hosono O, Kawasaki H, Tanaka H, Dang NH, Watanabe T, Arima N, Morimoto C: HTLV-I Tax induces and associates with Crk-associated substrate lymphocyte type (Cas-L). Oncogene. 2005, 24: 1262-1271.

    CAS  PubMed  Google Scholar 

  216. 216.

    Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C: Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes. J Exp Med. 1996, 184: 1365-1375.

    CAS  PubMed  Google Scholar 

  217. 217.

    Miyake-Nishijima R, Iwata S, Saijo S, Kobayashi H, Kobayashi S, Souta-Kuribara A, Hosono O, Kawasaki H, Tanaka H, Ikeda E, Okada Y, Iwakura Y, Morimoto C: Role of Crk-associated substrate lymphocyte type in the pathophysiology of rheumatoid arthritis in tax transgenic mice and in humans. Arthritis Rheum. 2003, 48: 1890-1900.

    CAS  PubMed  Google Scholar 

  218. 218.

    Harper JV, Brooks G: The mammalian cell cycle: an overview. Methods Mol Biol. 2005, 296: 113-153.

    CAS  PubMed  Google Scholar 

  219. 219.

    Jeang KT, Giam CZ, Majone F, Aboud M: Life, death, and tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation. J Biol Chem. 2004, 279: 31991-31994.

    CAS  PubMed  Google Scholar 

  220. 220.

    Marriott SJ, Semmes OJ: Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response. Oncogene. 2005, 24: 5986-5995.

    CAS  PubMed  Google Scholar 

  221. 221.

    Haller K, Wu Y, Derow E, Schmitt I, Jeang KT, Grassmann R: Physical interaction of human T-cell leukemia virus type 1 Tax with cyclin-dependent kinase 4 stimulates the phosphorylation of retinoblastoma protein. Mol Cell Biol. 2002, 22: 3327-3338.

    PubMed Central  CAS  PubMed  Google Scholar 

  222. 222.

    Haller K, Ruckes T, Schmitt I, Saul D, Derow E, Grassmann R: Tax-dependent stimulation of G1 phase-specific cyclin-dependent kinases and increased expression of signal transduction genes characterize HTLV type 1-transformed T cells. AIDS Res Hum Retroviruses. 2000, 16: 1683-1688.

    CAS  PubMed  Google Scholar 

  223. 223.

    Fraedrich K, Muller B, Grassmann R: The HTLV-1 Tax protein binding domain of cyclin-dependent kinase 4 (CDK4) includes the regulatory PSTAIRE helix. Retrovirology. 2005, 2: 54-

    PubMed Central  PubMed  Google Scholar 

  224. 224.

    Neuveut C, Low KG, Maldarelli F, Schmitt I, Majone F, Grassmann R, Jeang KT: Human T-cell leukemia virus type 1 Tax and cell cycle progression: role of cyclin D-cdk and p110Rb. Mol Cell Biol. 1998, 18: 3620-3632.

    PubMed Central  CAS  PubMed  Google Scholar 

  225. 225.

    Suzuki T, Kitao S, Matsushime H, Yoshida M: HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4. EMBO J. 1996, 15: 1607-1614.

    PubMed Central  CAS  PubMed  Google Scholar 

  226. 226.

    Suzuki T, Yoshida M: HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16Ink4a and counteracts its inhibitory activity to CDK4. Leukemia. 1997, 11 Suppl 3: 14-16.

    CAS  PubMed  Google Scholar 

  227. 227.

    Low KG, Dorner LF, Fernando DB, Grossman J, Jeang KT, Comb MJ: Human T-cell leukemia virus type 1 Tax releases cell cycle arrest induced by p16INK4a. J Virol. 1997, 71: 1956-1962.

    PubMed Central  CAS  PubMed  Google Scholar 

  228. 228.

    Suzuki T, Narita T, Uchida-Toita M, Yoshida M: Down-regulation of the INK4 family of cyclin-dependent kinase inhibitors by tax protein of HTLV-1 through two distinct mechanisms. Virology. 1999, 259: 384-391.

    CAS  PubMed  Google Scholar 

  229. 229.

    Kehn K, Fuente CL, Strouss K, Berro R, Jiang H, Brady J, Mahieux R, Pumfery A, Bottazzi ME, Kashanchi F: The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation. Oncogene. 2005, 24: 525-540.

    CAS  PubMed  Google Scholar 

  230. 230.

    Lemoine FJ, Marriott SJ: Accelerated G(1) phase progression induced by the human T cell leukemia virus type I (HTLV-I) Tax oncoprotein. J Biol Chem. 2001, 276: 31851-31857.

    CAS  PubMed  Google Scholar 

  231. 231.

    Asquith B, Zhang Y, Mosley AJ, de Lara CM, Wallace DL, Worth A, Kaftantzi L, Meekings K, Griffin GE, Tanaka Y, Tough DF, Beverley PC, Taylor GP, Macallan DC, Bangham CR: In vivo T lymphocyte dynamics in humans and the impact of human T-lymphotropic virus 1 infection. Proc Natl Acad Sci U S A. 2007, 104: 8035-8040.

    PubMed Central  CAS  PubMed  Google Scholar 

  232. 232.

    Zhou BB, Elledge SJ: The DNA damage response: putting checkpoints in perspective. Nature. 2000, 408: 433-439.

    CAS  PubMed  Google Scholar 

  233. 233.

    Zhou BB, Anderson HJ, Roberge M: Targeting DNA checkpoint kinases in cancer therapy. Cancer Biol Ther. 2003, 2: S16-S22.

    CAS  PubMed  Google Scholar 

  234. 234.

    Niida H, Nakanishi M: DNA damage checkpoints in mammals. Mutagenesis. 2006, 21: 3-9.

    CAS  PubMed  Google Scholar 

  235. 235.

    Marriott SJ, Lemoine FJ, Jeang KT: Damaged DNA and miscounted chromosomes: human T cell leukemia virus type I tax oncoprotein and genetic lesions in transformed cells. J Biomed Sci. 2002, 9: 292-298.

    CAS  PubMed  Google Scholar 

  236. 236.

    Majone F, Jeang KT: Clastogenic effect of the human T-cell leukemia virus type I Tax oncoprotein correlates with unstabilized DNA breaks. J Biol Chem. 2000, 275: 32906-32910.

    CAS  PubMed  Google Scholar 

  237. 237.

    Majone F, Luisetto R, Zamboni D, Iwanaga Y, Jeang KT: Ku protein as a potential human T-cell leukemia virus type 1 (HTLV-1) Tax target in clastogenic chromosomal instability of mammalian cells. Retrovirology. 2005, 2: 45-

    PubMed Central  PubMed  Google Scholar 

  238. 238.

    Branzei D, Foiani M: Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 2008, 9: 297-308.

    CAS  PubMed  Google Scholar 

  239. 239.

    Haoudi A, Daniels RC, Wong E, Kupfer G, Semmes OJ: Human T-cell leukemia virus-I tax oncoprotein functionally targets a subnuclear complex involved in cellular DNA damage-response. J Biol Chem. 2003, 278: 37736-37744.

    CAS  PubMed  Google Scholar 

  240. 240.

    Park HU, Jeong JH, Chung JH, Brady JN: Human T-cell leukemia virus type 1 Tax interacts with Chk1 and attenuates DNA-damage induced G2 arrest mediated by Chk1. Oncogene. 2004, 23: 4966-4974.

    CAS  PubMed  Google Scholar 

  241. 241.

    Park HU, Jeong SJ, Jeong JH, Chung JH, Brady JN: Human T-cell leukemia virus type 1 Tax attenuates gamma-irradiation-induced apoptosis through physical interaction with Chk2. Oncogene. 2006, 25: 438-447.

    CAS  PubMed  Google Scholar 

  242. 242.

    Gupta SK, Guo X, Durkin SS, Fryrear KF, Ward MD, Semmes OJ: Human T-cell leukemia virus type 1 Tax oncoprotein prevents DNA damage-induced chromatin egress of hyperphosphorylated Chk2. J Biol Chem. 2007, 282: 29431-29440.

    CAS  PubMed  Google Scholar 

  243. 243.

    Liang MH, Geisbert T, Yao Y, Hinrichs SH, Giam CZ: Human T-lymphotropic virus type 1 oncoprotein tax promotes S-phase entry but blocks mitosis. J Virol. 2002, 76: 4022-4033.

    PubMed Central  CAS  PubMed  Google Scholar 

  244. 244.

    Li J, Stern DF: DNA damage regulates Chk2 association with chromatin. J Biol Chem. 2005, 280: 37948-37956.

    CAS  PubMed  Google Scholar 

  245. 245.

    Nigg EA: Centrosome aberrations: cause or consequence of cancer progression?. Nat Rev Cancer. 2002, 2: 815-825.

    CAS  PubMed  Google Scholar 

  246. 246.

    Nitta T, Kanai M, Sugihara E, Tanaka M, Sun B, Nagasawa T, Sonoda S, Saya H, Miwa M: Centrosome amplification in adult T-cell leukemia and human T-cell leukemia virus type 1 Tax-induced human T cells. Cancer Sci. 2006, 97: 836-841.

    CAS  PubMed  Google Scholar 

  247. 247.

    Kramer A, Neben K, Ho AD: Centrosome replication, genomic instability and cancer. Leukemia. 2002, 16: 767-775.

    CAS  PubMed  Google Scholar 

  248. 248.

    Fukasawa K: Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer. 2007, 7: 911-924.

    CAS  PubMed  Google Scholar 

  249. 249.

    Peloponese JM, Haller K, Miyazato A, Jeang KT: Abnormal centrosome amplification in cells through the targeting of Ran-binding protein-1 by the human T cell leukemia virus type-1 Tax oncoprotein. Proc Natl Acad Sci U S A. 2005, 102: 18974-18979.

    PubMed Central  CAS  PubMed  Google Scholar 

  250. 250.

    Ching YP, Chan SF, Jeang KT, Jin DY: The retroviral oncoprotein Tax targets the coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication. Nat Cell Biol. 2006, 8: 717-724.

    CAS  PubMed  Google Scholar 

  251. 251.

    Guarguaglini G, Renzi L, D'Ottavio F, Di Fiore B, Casenghi M, Cundari E, Lavia P: Regulated Ran-binding protein 1 activity is required for organization and function of the mitotic spindle in mammalian cells in vivo. Cell Growth Differ. 2000, 11: 455-465.

    CAS  PubMed  Google Scholar 

  252. 252.

    Di Fiore B, Ciciarello M, Mangiacasale R, Palena A, Tassin AM, Cundari E, Lavia P: Mammalian RanBP1 regulates centrosome cohesion during mitosis. J Cell Sci. 2003, 116: 3399-3411.

    CAS  PubMed  Google Scholar 

  253. 253.

    Wong C, Stearns T: Centrosome number is controlled by a centrosome-intrinsic block to reduplication. Nat Cell Biol. 2003, 5: 539-544.

    CAS  PubMed  Google Scholar 

  254. 254.

    Malmanche N, Maia A, Sunkel CE: The spindle assembly checkpoint: preventing chromosome mis-segregation during mitosis and meiosis. FEBS Lett. 2006, 580: 2888-2895.

    CAS  PubMed  Google Scholar 

  255. 255.

    Bharadwaj R, Qi W, Yu H: Identification of two novel components of the human NDC80 kinetochore complex. J Biol Chem. 2004, 279: 13076-13085.

    CAS  PubMed  Google Scholar 

  256. 256.

    Yu H: Cdc20: a WD40 activator for a cell cycle degradation machine. Mol Cell. 2007, 27: 3-16.

    CAS  PubMed  Google Scholar 

  257. 257.

    Kasai T, Iwanaga Y, Iha H, Jeang KT: Prevalent loss of mitotic spindle checkpoint in adult T-cell leukemia confers resistance to microtubule inhibitors. J Biol Chem. 2002, 277: 5187-5193.

    CAS  PubMed  Google Scholar 

  258. 258.

    Jin DY, Spencer F, Jeang KT: Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell. 1998, 93: 81-91.

    CAS  PubMed  Google Scholar 

  259. 259.

    Yu H: Structural activation of Mad2 in the mitotic spindle checkpoint: the two-state Mad2 model versus the Mad2 template model. J Cell Biol. 2006, 173: 153-157.

    PubMed Central  CAS  PubMed  Google Scholar 

  260. 260.

    Liu B, Hong S, Tang Z, Yu H, Giam CZ: HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule. Proc Natl Acad Sci U S A. 2005, 102: 63-68.

    PubMed Central  CAS  PubMed  Google Scholar 

  261. 261.

    Liu B, Liang MH, Kuo YL, Liao W, Boros I, Kleinberger T, Blancato J, Giam CZ: Human T-lymphotropic virus type 1 oncoprotein tax promotes unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1 and causes chromosomal instability. Mol Cell Biol. 2003, 23: 5269-5281.

    PubMed Central  CAS  PubMed  Google Scholar 

  262. 262.

    Kuo YL, Giam CZ: Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence. EMBO J. 2006, 25: 1741-1752.

    PubMed Central  CAS  PubMed  Google Scholar 

  263. 263.

    Merling R, Chen C, Hong S, Zhang L, Liu M, Kuo YL, Giam CZ: HTLV-1 Tax mutants that do not induce G1 arrest are disabled in activating the anaphase promoting complex. Retrovirology. 2007, 4: 35-

    PubMed Central  PubMed  Google Scholar 

  264. 264.

    Sheleg SV, Peloponese JM, Chi YH, Li Y, Eckhaus M, Jeang KT: Evidence for cooperative transforming activity of the human pituitary tumor transforming gene and human T-cell leukemia virus type 1 Tax. J Virol. 2007, 81: 7894-7901.

    PubMed Central  CAS  PubMed  Google Scholar 

  265. 265.

    Craven SE, Bredt DS: PDZ proteins organize synaptic signaling pathways. Cell. 1998, 93: 495-498.

    CAS  PubMed  Google Scholar 

  266. 266.

    Fanning AS, Anderson JM: Protein modules as organizers of membrane structure. Curr Opin Cell Biol. 1999, 11: 432-439.

    CAS  PubMed  Google Scholar 

  267. 267.

    Fanning AS, Anderson JM: PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J Clin Invest. 1999, 103: 767-772.

    PubMed Central  CAS  PubMed  Google Scholar 

  268. 268.

    Rousset R, Fabre S, Desbois C, Bantignies F, Jalinot P: The C-terminus of the HTLV-1 Tax oncoprotein mediates interaction with the PDZ domain of cellular proteins. Oncogene. 1998, 16: 643-654.

    CAS  PubMed  Google Scholar 

  269. 269.

    Wilson KC, Center DM, Cruikshank WW, Zhang Y: Binding of HTLV-1 tax oncoprotein to the precursor of interleukin-16, a T cell PDZ domain-containing protein. Virology. 2003, 306: 60-67.

    CAS  PubMed  Google Scholar 

  270. 270.

    Lee SS, Weiss RS, Javier RT: Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein. Proc Natl Acad Sci U S A. 1997, 94: 6670-6675.

    PubMed Central  CAS  PubMed  Google Scholar 

  271. 271.

    Suzuki T, Ohsugi Y, Uchida-Toita M, Akiyama T, Yoshida M: Tax oncoprotein of HTLV-1 binds to the human homologue of Drosophila discs large tumor suppressor protein, hDLG, and perturbs its function in cell growth control. Oncogene. 1999, 18: 5967-5972.

    CAS  PubMed  Google Scholar 

  272. 272.

    Reynaud C, Fabre S, Jalinot P: The PDZ protein TIP-1 interacts with the Rho effector rhotekin and is involved in Rho signaling to the serum response element. J Biol Chem. 2000, 275: 33962-33968.

    CAS  PubMed  Google Scholar 

  273. 273.

    Ohashi M, Sakurai M, Higuchi M, Mori N, Fukushi M, Oie M, Coffey RJ, Yoshiura K, Tanaka Y, Uchiyama M, Hatanaka M, Fujii M: Human T-cell leukemia virus type 1 Tax oncoprotein induces and interacts with a multi-PDZ domain protein, MAGI-3. Virology. 2004, 320: 52-62.

    CAS  PubMed  Google Scholar 

  274. 274.

    Cheng H, Cenciarelli C, Shao Z, Vidal M, Parks WP, Pagano M, Cheng-Mayer C: Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70. Curr Biol. 2001, 11: 1771-1775.

    CAS  PubMed  Google Scholar 

  275. 275.

    Arpin-Andre C, Mesnard JM: The PDZ domain-binding motif of the human T cell leukemia virus type 1 tax protein induces mislocalization of the tumor suppressor hScrib in T cells. J Biol Chem. 2007, 282: 33132-33141.

    CAS  PubMed  Google Scholar 

  276. 276.

    Hirata A, Higuchi M, Niinuma A, Ohashi M, Fukushi M, Oie M, Akiyama T, Tanaka Y, Gejyo F, Fujii M: PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein augments the transforming activity in a rat fibroblast cell line. Virology. 2004, 318: 327-336.

    CAS  PubMed  Google Scholar 

  277. 277.

    Ishidate T, Matsumine A, Toyoshima K, Akiyama T: The APC-hDLG complex negatively regulates cell cycle progression from the G0/G1 to S phase. Oncogene. 2000, 19: 365-372.

    CAS  PubMed  Google Scholar 

  278. 278.

    Senda T, Shimomura A, Iizuka-Kogo A: Adenomatous polyposis coli (Apc) tumor suppressor gene as a multifunctional gene. Anat Sci Int. 2005, 80: 121-131.

    CAS  PubMed  Google Scholar 

  279. 279.

    Krummel MF, Macara I: Maintenance and modulation of T cell polarity. Nat Immunol. 2006, 7: 1143-1149.

    CAS  PubMed  Google Scholar 

  280. 280.

    Ishioka K, Higuchi M, Takahashi M, Yoshida S, Oie M, Tanaka Y, Takahashi S, Xie L, Green PL, Fujii M: Inactivation of tumor suppressor Dlg1 augments transformation of a T-cell line induced by human T-cell leukemia virus type 1 Tax protein. Retrovirology. 2006, 3: 71-

    PubMed Central  PubMed  Google Scholar 

  281. 281.

    Tsubata C, Higuchi M, Takahashi M, Oie M, Tanaka Y, Gejyo F, Fujii M: PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein is essential for the interleukin 2 independent growth induction of a T-cell line. Retrovirology. 2005, 2: 46-

    PubMed Central  PubMed  Google Scholar 

  282. 282.

    Xie L, Yamamoto B, Haoudi A, Semmes OJ, Green PL: PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo. Blood. 2006, 107: 1980-1988.

    PubMed Central  CAS  PubMed  Google Scholar 

  283. 283.

    Endo K, Hirata A, Iwai K, Sakurai M, Fukushi M, Oie M, Higuchi M, Hall WW, Gejyo F, Fujii M: Human T-cell leukemia virus type 2 (HTLV-2) Tax protein transforms a rat fibroblast cell line but less efficiently than HTLV-1 Tax. J Virol. 2002, 76: 2648-2653.

    PubMed Central  CAS  PubMed  Google Scholar 

  284. 284.

    Smith MR, Greene WC: Characterization of a novel nuclear localization signal in the HTLV-I tax transactivator protein. Virology. 1992, 187: 316-320.

    CAS  PubMed  Google Scholar 

  285. 285.

    Burton M, Upadhyaya CD, Maier B, Hope TJ, Semmes OJ: Human T-cell leukemia virus type 1 Tax shuttles between functionally discrete subcellular targets. J Virol. 2000, 74: 2351-2364.

    PubMed Central  CAS  PubMed  Google Scholar 

  286. 286.

    Alefantis T, Barmak K, Harhaj EW, Grant C, Wigdahl B: Characterization of a nuclear export signal within the human T cell leukemia virus type I transactivator protein Tax. J Biol Chem. 2003, 278: 21814-21822.

    CAS  PubMed  Google Scholar 

  287. 287.

    Alefantis T, Mostoller K, Jain P, Harhaj E, Grant C, Wigdahl B: Secretion of the human T cell leukemia virus type I transactivator protein tax. J Biol Chem. 2005, 280: 17353-17362.

    CAS  PubMed  Google Scholar 

  288. 288.

    Marriott SJ, Lindholm PF, Reid RL, Brady JN: Soluble HTLV-I Tax1 protein stimulates proliferation of human peripheral blood lymphocytes. New Biol. 1991, 3: 678-686.

    CAS  PubMed  Google Scholar 

  289. 289.

    Jain P, Mostoller K, Flaig KE, Ahuja J, Lepoutre V, Alefantis T, Khan ZK, Wigdahl B: Identification of human T cell leukemia virus type 1 tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein. J Biol Chem. 2007, 282: 34581-34593.

    CAS  PubMed  Google Scholar 

  290. 290.

    Tsuji T, Sheehy N, Gautier VW, Hayakawa H, Sawa H, Hall WW: The nuclear import of the human T lymphotropic virus type I (HTLV-1) tax protein is carrier- and energy-independent. J Biol Chem. 2007, 282: 13875-13883.

    CAS  PubMed  Google Scholar 

  291. 291.

    Gatza ML, Marriott SJ: Genotoxic stress and cellular stress alter the subcellular distribution of human T-cell leukemia virus type 1 tax through a CRM1-dependent mechanism. J Virol. 2006, 80: 6657-6668.

    PubMed Central  CAS  PubMed  Google Scholar 

  292. 292.

    Gatza ML, Dayaram T, Marriott SJ: Ubiquitination of HTLV-I Tax in response to DNA damage regulates nuclear complex formation and nuclear export. Retrovirology. 2007, 4: 95-

    PubMed Central  PubMed  Google Scholar 

  293. 293.

    Alefantis T, Flaig KE, Wigdahl B, Jain P: Interaction of HTLV-1 Tax protein with calreticulin: implications for Tax nuclear export and secretion. Biomed Pharmacother. 2007, 61: 194-200.

    PubMed Central  CAS  PubMed  Google Scholar 

  294. 294.

    Fried H, Kutay U: Nucleocytoplasmic transport: taking an inventory. Cell Mol Life Sci. 2003, 60: 1659-1688.

    CAS  PubMed  Google Scholar 

  295. 295.

    Terry LJ, Shows EB, Wente SR: Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science. 2007, 318: 1412-1416.

    CAS  PubMed  Google Scholar 

  296. 296.

    Hutten S, Kehlenbach RH: CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol. 2007, 17: 193-201.

    CAS  PubMed  Google Scholar 

  297. 297.

    Alefantis T, Jain P, Ahuja J, Mostoller K, Wigdahl B: HTLV-1 Tax nucleocytoplasmic shuttling, interaction with the secretory pathway, extracellular signaling, and implications for neurologic disease. J Biomed Sci. 2005, 12: 961-974.

    CAS  PubMed  Google Scholar 

  298. 298.

    Holaska JM, Black BE, Love DC, Hanover JA, Leszyk J, Paschal BM: Calreticulin Is a receptor for nuclear export. J Cell Biol. 2001, 152: 127-140.

    PubMed Central  CAS  PubMed  Google Scholar 

  299. 299.

    Goren I, Semmes OJ, Jeang KT, Moelling K: The amino terminus of Tax is required for interaction with the cyclic AMP response element binding protein. J Virol. 1995, 69: 5806-5811.

    PubMed Central  CAS  PubMed  Google Scholar 

  300. 300.

    Twizere JC, Springael JY, Boxus M, Burny A, Dequiedt F, Dewulf JF, Duchateau J, Portetelle D, Urbain P, Van Lint C, Green PL, Mahieux R, Parmentier M, Willems L, Kettmann R: Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling. Blood. 2007, 109: 1051-1060.

    PubMed Central  CAS  PubMed  Google Scholar 

  301. 301.

    Xiao G, Harhaj EW, Sun SC: Domain-specific interaction with the I kappa B kinase (IKK)regulatory subunit IKK gamma is an essential step in tax-mediated activation of IKK. J Biol Chem. 2000, 275: 34060-34067.

    CAS  PubMed  Google Scholar 

  302. 302.

    Basbous J, Bazarbachi A, Granier C, Devaux C, Mesnard JM: The central region of human T-cell leukemia virus type 1 Tax protein contains distinct domains involved in subunit dimerization. J Virol. 2003, 77: 13028-13035.

    PubMed Central  CAS  PubMed  Google Scholar 

  303. 303.

    Chun AC, Zhou Y, Wong CM, Kung HF, Jeang KT, Jin DY: Coiled-coil motif as a structural basis for the interaction of HTLV type 1 Tax with cellular cofactors. AIDS Res Hum Retroviruses. 2000, 16: 1689-1694.

    CAS  PubMed  Google Scholar 

  304. 304.

    Semmes OJ, Jeang KT: Definition of a minimal activation domain in human T-cell leukemia virus type I Tax. J Virol. 1995, 69: 1827-1833.

    PubMed Central  CAS  PubMed  Google Scholar 

  305. 305.

    Asquith B, Bangham CR: How does HTLV-I persist despite a strong cell-mediated immune response?. Trends Immunol. 2008, 29: 4-11.

    CAS  PubMed  Google Scholar 

  306. 306.

    Kaul R, Verma SC, Robertson ES: Protein complexes associated with the Kaposi's sarcoma-associated herpesvirus-encoded LANA. Virology. 2007, 364: 317-329.

    PubMed Central  CAS  PubMed  Google Scholar 

  307. 307.

    Berk AJ: Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus. Oncogene. 2005, 24: 7673-7685.

    CAS  PubMed  Google Scholar 

  308. 308.

    Gallimore PH, Turnell AS: Adenovirus E1A: remodelling the host cell, a life or death experience. Oncogene. 2001, 20: 7824-7835.

    CAS  PubMed  Google Scholar 

  309. 309.

    Bex F, McDowall A, Burny A, Gaynor R: The human T-cell leukemia virus type 1 transactivator protein Tax colocalizes in unique nuclear structures with NF-kappaB proteins. J Virol. 1997, 71: 3484-3497.

    PubMed Central  CAS  PubMed  Google Scholar 

  310. 310.

    Radivojac P, Iakoucheva LM, Oldfield CJ, Obradovic Z, Uversky VN, Dunker AK: Intrinsic disorder and functional proteomics. Biophys J. 2007, 92: 1439-1456.

    PubMed Central  CAS  PubMed  Google Scholar 

  311. 311.

    Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN: Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J. 2005, 272: 5129-5148.

    CAS  PubMed  Google Scholar 

  312. 312.

    Kim PM, Sboner A, Xia Y, Gerstein M: The role of disorder in interaction networks: a structural analysis. Mol Syst Biol. 2008, 4: 179-

    PubMed Central  PubMed  Google Scholar 

  313. 313.

    Han JD, Bertin N, Hao T, Goldberg DS, Berriz GF, Zhang LV, Dupuy D, Walhout AJ, Cusick ME, Roth FP, Vidal M: Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature. 2004, 430: 88-93.

    CAS  PubMed  Google Scholar 

  314. 314.

    Uversky VN, Roman A, Oldfield CJ, Dunker AK: Protein intrinsic disorder and human papillomaviruses: increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs. J Proteome Res. 2006, 5: 1829-1842.

    CAS  PubMed  Google Scholar 

  315. 315.

    Durkin SS, Ward MD, Fryrear KA, Semmes OJ: Site-specific phosphorylation differentiates active from inactive forms of the human T-cell leukemia virus type 1 Tax oncoprotein. J Biol Chem. 2006, 281: 31705-31712.

    CAS  PubMed  Google Scholar 

  316. 316.

    Kashanchi F, Brady JN: Transcriptional and post-transcriptional gene regulation of HTLV-1. Oncogene. 2005, 24: 5938-5951.

    CAS  PubMed  Google Scholar 

  317. 317.

    Beraud C, Sun SC, Ganchi P, Ballard DW, Greene WC: Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency. Mol Cell Biol. 1994, 14: 1374-1382.

    PubMed Central  CAS  PubMed  Google Scholar 

  318. 318.

    Yang X, Wang JS, Han H: [Interaction between HTLV-1 transcription activator tax and Taxreb107]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002, 34: 231-235.

    CAS  Google Scholar 

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This work was supported by the Sixth Research Framework Programme of the European Union (project INCA LSHC-CT-2005-018704), the Belgian Foundation against Cancer, the Bekales Foundation, and the "Fonds National de la Recherche Scientifique" (FRS-FNRS and Télévie). MB ("FRIA" fellow), SL ("FRIA" fellow), RK (Research Director), LW (Research Director), JCT (Post-doctoral fellow) and JFD (Technician) are members of the FNRS. We thank Françoise Bex for comments and suggestions.

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Correspondence to Luc Willems.

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The authors declare that they have no competing interests.

Authors' contributions

MB and LW collected data from the literature and wrote the paper, JT, SL and RK suggested comments, FD provided technical help. All authors read and approved the final manuscript.

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Boxus, M., Twizere, JC., Legros, S. et al. The HTLV-1 Tax interactome. Retrovirology 5, 76 (2008).

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