- Open Access
HTLV-1 Tax: centrosome amplification and cancer
© Pumfery et al; licensee BioMed Central Ltd. 2006
Received: 18 July 2006
Accepted: 09 August 2006
Published: 09 August 2006
During interphase, each cell contains a single centrosome that acts as a microtubule organizing center for cellular functions in interphase and in mitosis. Centrosome amplification during the S phase of the cell cycle is a tightly regulated process to ensure that each daughter cell receives the proper complement of the genome. The controls that ensure that centrosomes are duplicated exactly once in the cell cycle are not well understood. In solid tumors and hematological malignancies, centrosome abnormalities resulting in aneuploidy is observed in the majority of cancers. These phenotypes are also observed in cancers induced by viruses, including adult T cell lymphoma which is caused by the human T cell lymphotrophic virus Type 1 (HTLV-1). Several reports have indicated that the HTLV-1 transactivator, Tax, is directly responsible for the centrosomal abnormalities observed in ATL cells. A recent paper in Nature Cell Biology by Ching et al. has shed some new light into how Tax may be inducing centrosome abnormalities. The authors demonstrated that 30% of ATL cells contained more than two centrosomes and expression of Tax alone induced supernumerary centrosomes. A cellular coiled-coil protein, Tax1BP2, was shown to interact with Tax and disruption of this interaction led to failure of Tax to induce centrosome amplification. Additionally, down-regulation of Tax1BP2 led to centrosome amplification. These results suggest that Tax1BP2 may be an important block to centrosome re-duplication that is observed in normal cells. Presently, a specific cellular protein that prevents centrosome re-duplication has not been identified. This paper has provided further insight into how Tax induces centrosome abnormalities that lead to ATL. Lastly, additional work on Tax1BP2 will also provide insight into how the cell suppresses centrosome re-duplication during the cell cycle and the role that Tax1BP2 plays in this important cellular pathway.
Faithful duplication of the genetic content of cells and proper segregation into two daughter cells are two highly regulated and distinct processes. The cell cycle determines when cells will duplicate their genome and the four phases are regulated by a series of different cyclin/cyclin-dependent kinase complexes. Duplication of the genome occurs during the S phase while segregation of duplicated chromosomes into daughter cells occurs during the M (mitotic) phase. Proper segregation of chromosomes during M phase requires that the centrosomes are faithfully duplicated prior to mitosis. Duplication of centrosomes occurs at the end of G1 and the beginning of the S phase, yet is regulated separately from the duplication of the genome. Dysregulation of either the cell cycle or centrosome duplication can result in major genetic alterations and cancer [1–3]. Changes in centrosome duplication have been observed in cancers caused by genetic mutations as well as in cancers induced by viruses. A recent report by Ching et al.  further elucidates how the HTLV-1 Tax protein may modulate centrosome duplication resulting in aneuploidy and the development of adult T cell leukemia (ATL).
The centrosome functions as the microtubule organizing center (MTOC) of the cell and modulates the microtubule network critical for chromosome segregation, cell division, intracellular transport, and development [1–3]. The centrosome is composed of a pair of centrioles surrounded by the pericentriolar material [1, 2], which is composed of at least 50 different proteins including several different tubulins, centrin, and proteins containing a coiled-coil motif . To prepare for chromosome segregation in the next M phase, a single centrosome needs to be duplicated. During the G0 and G1 phases of the cell cycle there is a single centrosome that is inherited from the mother cell during the previous cell division, which is duplicated during the late G1 and S phases. During mitosis, the number of spindle poles is generally determined by the number of centrosomes .
Centrosome duplication occurs in a semi-conservative manner and consists of four phases: (i) centriole splitting in which the mother and daughter centrioles detach; (ii) semiconservative centrosome duplication, where a new centriole is formed adjacent to the original centriole; (iii) maturation involves recruitment of pericentriolar material proteins; and (iv) centrosome separation during mitosis to form the spindle poles [1, 2]. Centrosome duplication is regulated by a series of phosphorylation and dephosphorylation events mediated by several kinases including Cdk2, Nek2, polo-like kinases, and aurora kinases [1, 2, 5]. The coordination between replication and centrosome duplication suggests that these events may be regulated by a common mechanism. Cdk2 is attractive as the central modulator since it is involved in both processes. Cdk2 is activated by binding to Cyclin E or Cyclin A at the start of S phase to induce DNA replication. Additionally, Cdk2 is required for centrosome duplication in a variety of cell systems [2, 6]. Centrosomes are duplicated only once during each cell cycle and there is an apparent intrinsic block to reduplication of centrosomes . However, the nature of this block is not known, but it apparently is overcome in cancer. Increased centrosome numbers leads to disturbances in mitosis and cytokinesis leading to errors in chromosome segregation and chromosome instability .
Alterations in centrosome duplication and the resulting aneuploidy are observed in a significant number of cancers. There are several possible mechanisms of centrosome amplification, including: (i) centrosome duplication more than once in a cell cycle; (ii) failure to undergo cytokinesis resulting in doubling of the genome ; and improper splitting, or fragmentation, of centrosomes in the M phase due to DNA damage . Centrosome amplification is frequently seen in a number of solid cancers including breast, lung, colon, prostate, testicular, and head and neck squamous cell carcinoma , as well as several hematological malignancies such as Hodgkin's lymphoma, multiple myeloma, and chronic lymphocytic leukemia . Some of the common genetic alterations in cancer associated with centrosome amplification include inactivation of p53, over-expression of Cyclin E , and mutation of BRCA1 [6, 10].
Effect of various viral proteins on centrosomal abnormalities
Cellular Interacting Protein
Function in Normal Cells
Nuclear export receptor
>2 centrosomes per cell
>2 centrosomes per cell
>2 centrosomes per cell
Abnormal mitotic spindles
>2 centrosomes per cell
Mitotic spindle checkpoint protein
Regulator of Ran-GTPase pathway
>2 centrosomes per cell
Regulates centrosome duplication
>2 centrosomes per cell
The HTLV-1 Tax protein contributes to the ability of the virus to cause ATL by inactivating p53 [21–24], altering the cell cycle [25, 26], and inactivating Rb . As Tax is able to deregulate cellular checkpoints, most notably the G1/S transition [28, 29], it is not surprising that this oncoprotein is involved in mitotic disruption. An early report demonstrated that expression of Tax alone was sufficient to induce both centric (containing a kinetochore and representative of segregation defects) and acentric (representative of DNA damage) micronuclei . While clastogenic effects induced by Tax appears to be due to subversion of DNA damage repair pathways [31–34], Tax involvement in aneugenic damage was less clear. A study by Jin et al.  indicated that the association of Tax with hsMAD1, a mitotic spindle checkpoint (MSC) protein, led to the translocation of both MAD1 and MAD2 to the cytoplasm. The MSC is necessary to halt the cell cycle when an error(s) in chromosome segregation is detected. When all of the kinetochores are attached to both poles of the mitotic spindle apparatus and chromosomes are equally segregated to opposite poles, the block is then released . By disrupting normal localization of these factors (i.e. MAD1 and MAD2) to kinetochores following chromosomal missegregation, Tax was able to usurp this checkpoint and thus allow for accumulation of multinucleated cells, a common phenotype of ATL cells. However, several questions remained including (i) was aneuploidogenic damage simply the accumulation of natural occurring mis-segregation events  due to Tax or (ii) were there other Tax-related mechanisms either direct or indirect, that induced aneugenic damage?
Evidence for the direct involvement of Tax in aneuploidy development was recently shown by Peloponese and colleagues . Tax was shown to localize to centrosomes during mitosis and interact with the Ran-GTPase pathway through the Ran-binding protein 1 (RanBP1). This protein complex regulates mitotic centrosome stability and microtubule nucleation and spindle formation [37, 38]. Interaction of Tax with RanBP1 was shown to be necessary for Tax targeting to centrosomes and induction of supernumerary centrosomes. The interaction of Tax with the Ran-GTPase pathway to dysregulate centrosome duplication is reminiscent of HBV X interaction with Crm1 , a Ran-GTP binding nuclear export receptor .
The involvement of Tax in centrosome amplification has been further strengthened by recent findings from Ching et al. . Tax was observed to localize to centrosomes in both transfected cells and HTLV-1 transformed cells. About 30% of ATL cells displayed centrosome amplification (>2 centrosomes) and 30–80% of cells expressing Tax alone had supernumerary centrosomes indicating that Tax was responsible for the abnormal centrosome phenotype in ATL. Through a yeast two-hybrid approach, Tax was shown to associate with a coiled-coil protein, Tax1BP2 (formerly known as TaxBP121). Tax1BP2 has high sequence similarity to C-Nap1 (centrosomal Nek2-associated protein 1), a protein involved in centrosome cohesion during the interphase of cell cycle , and was shown to be part of the centrosome complex. Tax interaction with Tax1BP2 was shown to be necessary for Tax to induce supernumerary centrosomes and over-expression of Tax1BP2 countered this effect. Additionally, down-regulation of Tax1BP2 expression by siRNAs resulted in amplification of centrosomes leading the authors to speculate that Tax1BP2 may be the intrinsic block to re-duplication proposed by Wong and Stearn . This interaction provides a novel way for Tax to induce aneuploidogenic damage through centrosome amplification. Furthermore, if Tax1BP2 proves to be important for the block to centrosome duplication this will be the first protein identified to perform such a function. However, several questions remain: (i) is there differential expression or localization of Tax1BP2 during the cell cycle; (ii) does knock-down of Tax1BP2 expression in the S and G2 phases allow for centrosome re-duplication; and more importantly (iii) how does Tax1BP2 function to limit amplification of centrosomes?
This work was supported by grants from the George Washington University REF funds to A. Vertes and F. Kashanchi, and NIH grants AI44357, AI43894 and 13969 to F.K.
- Hinchcliffe EH, Sluder G: "It takes two to tango": Understanding how centrosome duplication is regulated throughout the cell cycle. Genes Dev. 2001, 15: 1167-1181. 10.1101/gad.894001.View ArticlePubMedGoogle Scholar
- Wang Q, Hirohashi Y, Furuuchi K, Zhao H, Liu Q, Zhang H, Murali R, Berezov A, Du X, Li B, Greene MI: The centrosome in normal and transformed cells. DNA Cell Biol. 2004, 23: 475-489. 10.1089/1044549041562276.View ArticlePubMedGoogle Scholar
- Doxsey S, McCollum D, Theurkauf W: Centrosomes in cellular regulation. Annu Rev Cell Dev Biol. 2005, 21: 411-434. 10.1146/annurev.cellbio.21.122303.120418.View ArticlePubMedGoogle Scholar
- Ching Y, Chan S, Jeang K, Jin D: The retroviral oncoprotein tax targets the coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication. Nat Cell Biol. 2006, 8: 717-724. 10.1038/ncb1432.View ArticlePubMedGoogle Scholar
- Hinchcliffe EH, Sluder G: Centrosome duplication: Three kinases come up a winner!. Curr Biol. 2001, 11: R698-701. 10.1016/S0960-9822(01)00412-2.View ArticlePubMedGoogle Scholar
- Fukasawa K: Centrosome amplification, chromosome instability and cancer development. Cancer Lett. 2005, 230: 6-19. 10.1016/j.canlet.2004.12.028.View ArticlePubMedGoogle Scholar
- Wong C, Stearns T: Centrosome number is controlled by a centrosome-intrinsic block to reduplication. Nat Cell Biol. 2003, 5: 539-544. 10.1038/ncb993.View ArticlePubMedGoogle Scholar
- Hut HMJ, Lemstra W, Blaauw EH, Van Cappellen, Gert WA, Kampinga HH, Sibon OCM: Centrosomes split in the presence of impaired DNA integrity during mitosis. Mol Biol Cell. 2003, 14: 1993-2004. 10.1091/mbc.E02-08-0510.PubMed CentralView ArticlePubMedGoogle Scholar
- Krämer A, Neben K, Ho AD: Centrosome aberrations in hematological malignancies. Cell Biol Int. 2005, 29: 375-383. 10.1016/j.cellbi.2005.03.004.View ArticlePubMedGoogle Scholar
- Deng C: Roles of BRCA1 in centrosome duplication. Oncogene. 2002, 21: 6222-6227. 10.1038/sj.onc.1205713.View ArticlePubMedGoogle Scholar
- Forgues M, Difilippantonio MJ, Linke SP, Ried T, Nagashima K, Feden J, Valerie K, Fukasawa K, Wang XW: Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. Mol Cell Biol. 2003, 23: 5282-5292. 10.1128/MCB.23.15.5282-5292.2003.PubMed CentralView ArticlePubMedGoogle Scholar
- Forgues M, Marrogi AJ, Spillare EA, Wu CG, Yang Q, Yoshida M, Wang XW: Interaction of the hepatitis B virus X protein with the Crm1-dependent nuclear export pathway. J Biol Chem. 2001, 276: 22797-22803. 10.1074/jbc.M101259200.View ArticlePubMedGoogle Scholar
- Yun C, Cho H, Kim S, Lee J, Park SY, Chan GK, Cho H: Mitotic aberration coupled with centrosome amplification is induced by hepatitis B virus X oncoprotein via the ras-mitogen-activated protein/extracellular signal-regulated kinase-mitogen-activated protein pathway. Mol Cancer Res. 2004, 2: 159-169.PubMedGoogle Scholar
- Duensing S, Münger K: Centrosomes, genomic instability, and cervical carcinogenesis. Crit Rev Eukaryot Gene Expr. 2003, 13: 9-23. 10.1615/CritRevEukaryotGeneExpr.v13.i1.20.View ArticlePubMedGoogle Scholar
- Duensing S, Münger K: The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability. Cancer Res. 2002, 62: 7075-7082.PubMedGoogle Scholar
- Pan H, Zhou F, Gao S: Kaposi's sarcoma-associated herpesvirus induction of chromosome instability in primary human endothelial cells. Cancer Res. 2004, 64: 4064-4068. 10.1158/0008-5472.CAN-04-0657.View ArticlePubMedGoogle Scholar
- Si H, Robertson ES: Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen induces chromosomal instability through inhibition of p53 function. J Virol. 2006, 80: 697-709. 10.1128/JVI.80.2.697-709.2006.PubMed CentralView ArticlePubMedGoogle Scholar
- Nitta T, Kanai M, Sugihara E, Tanaka M, Sun B, Sonoda S, Miwa M, Nagasawa T: Centrosome amplification in adult T-cell leukemia and human T-cell leukemia virus type 1 tax-induced human T cells. Cancer Sci. 2006.Google Scholar
- Peloponese J, Haller K, Miyazato A, Jeang K: 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 USA. 2005, 102: 18974-18979. 10.1073/pnas.0506659103.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1016/S0092-8674(00)81148-4.View ArticlePubMedGoogle Scholar
- 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. 10.1093/carcin/bgi274.View ArticlePubMedGoogle Scholar
- Grassmann R, Aboud M, Jeang K: Molecular mechanisms of cellular transformation by HTLV-1 tax. Oncogene. 2005, 24: 5976-5985. 10.1038/sj.onc.1208978.View ArticlePubMedGoogle Scholar
- Jeong S, Pise-Masison CA, Radonovich MF, Park HU, Brady JN: Activated AKT regulates NF-kappaB activation, p53 inhibition and cell survival in HTLV-1-transformed cells. Oncogene. 2005, 24: 6719-6728. 10.1038/sj.onc.1208825.View ArticlePubMedGoogle Scholar
- Pise-Masison CA, Brady JN: Setting the stage for transformation: HTLV-1 tax inhibition of of p53 function. Front Biosci. 2005, 10: 919-930.View ArticlePubMedGoogle Scholar
- Kehn K, Berro R, de la Fuente C, Strouss K, Ghedin E, Dadgar S, Bottazzi ME, Pumfery A, Kashanchi F: Mechanisms of HTLV-1 transformation. Front Biosci. 2004, 9: 2347-2372.View ArticlePubMedGoogle Scholar
- Kehn K, Deng L, de la Fuente C, Strouss K, Wu K, Maddukuri A, Baylor S, Rufner R, Pumfery A, Bottazzi ME, Kashanchi F: The role of cyclin D2 and p21/waf1 in human T-cell leukemia virus type 1 infected cells. Retrovirology. 2004, 1: 6-6. 10.1186/1742-4690-1-6.PubMed CentralView ArticlePubMedGoogle Scholar
- Kehn K, Fuente Cdl, 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. 10.1038/sj.onc.1208105.View ArticlePubMedGoogle Scholar
- 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 CentralPubMedGoogle Scholar
- Schmitt I, Rosin O, Rohwer P, Gossen M, Grassmann R: Stimulation of cyclin-dependent kinase activity and G1- to S-phase transition in human lymphocytes by the human T-cell leukemia/lymphotropic virus type 1 tax protein. J Virol. 1998, 72: 633-640.PubMed CentralPubMedGoogle Scholar
- Majone F, Semmes OJ, Jeang KT: Induction of micronuclei by HTLV-I tax: A cellular assay for function. Virology. 1993, 193: 456-459. 10.1006/viro.1993.1145.View ArticlePubMedGoogle Scholar
- 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. 10.1074/jbc.C000538200.View ArticlePubMedGoogle Scholar
- Marriott SJ, Lemoine FJ, Jeang K: 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.View ArticlePubMedGoogle Scholar
- Jeang K, Giam C, 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. 10.1074/jbc.R400009200.View ArticlePubMedGoogle Scholar
- Majone F, Luisetto R, Zamboni D, Iwanaga Y, Jeang K: 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: 45-45. 10.1186/1742-4690-2-45.PubMed CentralView ArticlePubMedGoogle Scholar
- Chan GK, Liu S, Yen TJ: Kinetochore structure and function. Trends Cell Biol. 2005, 15: 589-598. 10.1016/j.tcb.2005.09.010.View ArticlePubMedGoogle Scholar
- Norppa H, Falck GC: What do human micronuclei contain?. Mutagenesis. 2003, 18: 221-233. 10.1093/mutage/18.3.221.View ArticlePubMedGoogle Scholar
- Zhang C, Hughes M, Clarke PR: Ran-GTP stabilises microtubule asters and inhibits nuclear assembly in xenopus egg extracts. J Cell Sci. 1999, 112 (Pt 14): 2453-2461.PubMedGoogle Scholar
- Di Fiore B, Ciciarello M, Mangiacasale R, Palena A, Tassin A, Cundari E, Lavia P: Mammalian RanBP1 regulates centrosome cohesion during mitosis. J Cell Sci. 2003, 116: 3399-3411. 10.1242/jcs.00624.View ArticlePubMedGoogle Scholar
- Arnaoutov A, Azuma Y, Ribbeck K, Joseph J, Boyarchuk Y, Karpova T, McNally J, Dasso M: Crm1 is a mitotic effector of ran-GTP in somatic cells. Nat Cell Biol. 2005, 7: 626-632. 10.1038/ncb1263.View ArticlePubMedGoogle Scholar
- Mayor T, Stierhof YD, Tanaka K, Fry AM, Nigg EA: The centrosomal protein C-Nap1 is required for cell cycle-regulated centrosome cohesion. J Cell Biol. 2000, 151: 837-846. 10.1083/jcb.151.4.837.PubMed CentralView ArticlePubMedGoogle Scholar
- Mori N, Fujii M, Hinz M, Nakayama K, Yamada Y, Ikeda S, Yamasaki Y, Kashanchi F, Tanaka Y, Tomonaga M, Yamamoto N: Activation of cyclin D1 and D2 promoters by human T-cell leukemia virus type I tax protein is associated with IL-2-independent growth of T cells. Int J Cancer. 2002, 99: 378-385. 10.1002/ijc.10388.View ArticlePubMedGoogle Scholar
- Santiago F, Clark E, Chong S, Molina C, Mozafari F, Mahieux R, Fujii M, Azimi N, Kashanchi F: Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1-infected cells. J Virol. 1999, 73: 9917-9927.PubMed CentralPubMedGoogle Scholar
- Akagi T, Ono H, Shimotohno K: Expression of cell-cycle regulatory genes in HTLV-I infected T-cell lines: Possible involvement of Tax1 in the altered expression of cyclin D2, p18Ink4 and p21Waf1/Cip1/Sdi1. Oncogene. 1996, 12: 1645-1652.PubMedGoogle Scholar
- Li J, Li H, Tsai M: Direct binding of the N-terminus of HTLV-1 tax oncoprotein to cyclin-dependent kinase 4 is a dominant path to stimulate the kinase activity. Biochemistry. 2003, 42: 6921-6928. 10.1021/bi034369n.View ArticlePubMedGoogle Scholar
- Fraedrich K, Müller B, Grassmann R: The HTLV-1 tax protein binding domain of cyclin-dependent kinase 4 (CDK4) includes the regulatory PSTAIRE helix. Retrovirology. 2005, 2: 54-54. 10.1186/1742-4690-2-54.PubMed CentralView ArticlePubMedGoogle Scholar
- Li J, Li H, Tsai MD: Direct binding of the N-terminus of HTLV-1 tax oncoprotein to cyclin-dependent kinase 4 is a dominant path to stimulate the kinase activity. Biochemistry (N Y). 2003, 42: 6921-6928.View ArticleGoogle Scholar
- 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. 10.1128/MCB.22.10.3327-3338.2002.PubMed CentralView ArticlePubMedGoogle Scholar
- 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 CentralView ArticlePubMedGoogle Scholar
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