Expression of parathyroid hormone-related protein during immortalization of human peripheral blood mononuclear cells by HTLV-1: Implications for transformation
© Nadella et al; licensee BioMed Central Ltd. 2008
Received: 10 March 2008
Accepted: 09 June 2008
Published: 09 June 2008
Adult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-lymphotropic virus type-1 (HTLV-1); however, additional host factors are also required for T-cell transformation and development of ATLL. The HTLV-1 Tax protein plays an important role in the transformation of T-cells although the exact mechanisms remain unclear. Parathyroid hormone-related protein (PTHrP) plays an important role in the pathogenesis of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of ATLL patients. However, PTHrP is also up-regulated in HTLV-1-carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients without hypercalcemia, indicating that PTHrP is expressed before transformation of T-cells. The expression of PTHrP and the PTH/PTHrP receptor during immortalization or transformation of lymphocytes by HTLV-1 has not been investigated.
We report that PTHrP was up-regulated during immortalization of lymphocytes from peripheral blood mononuclear cells by HTLV-1 infection in long-term co-culture assays. There was preferential utilization of the PTHrP-P2 promoter in the immortalized cells compared to the HTLV-1-transformed MT-2 cells. PTHrP expression did not correlate temporally with expression of HTLV-1 tax. HTLV-1 infection up-regulated the PTHrP receptor (PTH1R) in lymphocytes indicating a potential autocrine role for PTHrP. Furthermore, co-transfection of HTLV-1 expression plasmids and PTHrP P2/P3-promoter luciferase reporter plasmids demonstrated that HTLV-1 up-regulated PTHrP expression only mildly, indicating that other cellular factors and/or events are required for the very high PTHrP expression observed in ATLL cells. We also report that macrophage inflammatory protein-1α (MIP-1α), a cellular gene known to play an important role in the pathogenesis of HHM in ATLL patients, was highly expressed during early HTLV-1 infection indicating that, unlike PTHrP, its expression was enhanced due to activation of lymphocytes by HTLV-1 infection.
These data demonstrate that PTHrP and its receptor are up-regulated specifically during immortalization of T-lymphocytes by HTLV-1 infection and may facilitate the transformation process.
Human T-lymphotropic virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a variety of other disorders [1, 2]. ATLL is an aggressive malignancy of CD4+ T cells that occurs in approximately 5% of infected individuals after a long latency period of 20–40 years. The long latency period and the relatively low proportion of HTLV-1-infected people that develop ATLL reflect the inefficiency of the virus to transform cells and the need for multiple cooperative changes in growth control mechanisms to induce leukemogenesis.
HTLV-1 is a complex deltaretrovirus and its genome not only encodes for the essential viral genes gag, pol, and env, but also additional HTLV-1-specific regulatory proteins Tax and Rex, several accessory proteins p12, p13, p30 and a minus-strand encoded protein, HTLV-1 bZIP-factor (HBZ) . Although the precise mechanisms underlying transformation are not completely understood, the 40-kDa transcriptional transactivator, Tax, is thought to be principally responsible for tumorigenesis . The ability to activate cellular genes, including proto-oncogenes, is a key mechanism leading to immortalization and transformation of HTLV-1-infected cells. Rex regulates the expression of incompletely spliced viral RNAs by interacting with the Rex response element in the viral RNA and cellular proteins used by CRM-dependent nuclear export . Although Rex is not required for immortalization of lymphocytes in vitro, it is required for infectivity and persistence in vivo . The accessory genes p12, p30, p13 and HBZ contribute to establishing persistent viral infection in vivo but are not required for transformation of cells in vitro [17, 18].
About 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening paraneoplastic syndrome that occurs in a wide variety of cancers in addition to ATLL . ATLL cells express factors such as interleukin-1, tumor necrosis factor β, parathyroid hormone-related protein (PTHrP), macrophage inflammatory protein-1α (MIP-1α) and receptor activator of nuclear factor-κB ligand (RANKL) that directly and/or indirectly stimulate osteoclast differentiation and activity, resulting in hypercalcemia [20–24]. PTHrP has been shown to play a central role in the pathogenesis of HHM in ATLL patients, but likely has additive or synergistic effects with other tumor-associated cytokines . Although PTHrP was discovered based on its role in the pathogenesis of HHM, PTHrP is now known to be a complex factor with a broad range of physiologic and/or pathophysiologic actions in different tissues . PTHrP has been shown to be an auto/paracrine cell growth regulator that increases proliferation of several cell types including chondrocytes and renal epithelial cells . PTHrP stimulates proliferation through the PTH1R by mechanisms involving both PKA and PKC signaling pathways.
Watanabe et al have shown that PTHrP was constitutively expressed in HTLV-1-carriers and ATLL patients with or without hypercalcemia which suggests that PTHrP is expressed before transformation of lymphocytes . ATLL cell adhesion up-regulated PTHrP expression  indicating additional roles for PTHrP besides its central role in the pathogenesis of HHM. Moreover, PTHrP gene expression was induced during transformation of normal rat embryo fibroblasts by co-transfection with an activated ras gene and a mutated p53 gene . Insogna et al have shown that PTHrP induced transformation of rat fibroblasts with epidermal growth factor . In addition, co-transfection of rat embryonic fibroblasts with Tax and ras transformed the fibroblasts and they were highly tumorigenic in vivo . Based on these findings, it is possible that PTHrP functions as a transforming factor in conjunction with other oncogenes.
The goal of this study was to investigate the expression of PTHrP, its receptor, and MIP-1α during the early stages of immortalization of human lymphocytes by HTLV-1. Using long-term liquid culture immortalization assays, we showed that PTHrP and PTH1R were markedly up-regulated during immortalization of T-lymphocytes. PTHrP expression did not correlate temporally with HTLV-1 tax expression and IL-2 stimulation. Co-transfection of HTLV-1 with a PTHrP P2/P3 luciferase reporter showed that PTHrP was up-regulated by HTLV-1 infection.
HTLV-1-infected PBMCs proliferate beyond six weeks
PTHrP was up-regulated during immortalization of PBMCs with HTLV-1
Up-regulation of PTHrP was mediated by the PTHrP P2 and P3 promoters
HTLV-1 infection up-regulated PTH1R expression
PTHrP expression did not correlate with HTLV-1 tax expression
HTLV-1 and HTLV-1 Rex up-regulated PTHrP expression
MIP-1α expression correlated with activation of PBMCs following HTLV-1 infection
Although HTLV-1 Tax is known to have pleiotropic effects that either directly or indirectly contribute to immortalization and transformation of infected T-cells, the exact mechanisms of transformation are unclear. In this study, we analyzed the temporal PTHrP gene expression during virus-mediated immortalization of lymphocytes to characterize its role in the transformation process. We present data to show that PTHrP is markedly up-regulated during the immortalization process.
An important step in HTLV-1-induced leukemogenesis is the induction of abnormal T-cell growth. Long-term immortalization assays have been used to study the kinetics of HTLV-1 infection and abnormal T-cell growth that lead to transformation. The growth curves in our study are similar to previous reports [31, 38]. Human PBMCs that were cultured in the presence of IL-2, but not exposed to the virus, survived in vitro only for a few weeks. Following exposure to HTLV-1, PBMCs initially underwent a proliferative response due to HTLV-1 infection after which the cells entered a "growth crisis" between weeks 5–7 followed by expansion of immortalized cells. The high level of HTLV-1 p19 antigen expression in the first few weeks of co-culture was due to the live residual irradiated SLB-1 cells. However, the p19 expression after three weeks in culture was from the newly infected PBMCs and demonstrated active HTLV-1 viral infection (data not shown).
Our data showed that PTHrP mRNA expression was gradually up-regulated in PBMCs following HTLV-1 infection; however, marked expression of PTHrP protein occurred at the time when the PBMCs were undergoing immortalization. This supports an important role for PTHrP during immortalization and the subsequent transformation process. The differences between the levels of PTHrP mRNA and protein expression were likely due to differences in translation efficiency, processing of the mature protein, and/or its secretion from the cells. Regulation of PTHrP secretion is a complex process and it has been shown that some PTHrP may not be secreted but targeted directly to the nucleus and function in an intracrine fashion . Abundant expression of PTH1R is normally found in the target organs that regulate calcium ion homeostasis, such as the kidney and bone, with restricted expression in other tissues. This contrasts with the widespread expression of PTHrP. In our investigation, the marked induction of both PTHrP and PTH1R by HTLV-1 suggests that PTHrP functioned as an autocrine growth regulator in the transformation process.
PTHrP is a complex gene that is regulated by three distinct promoters, P1, P2 and P3, and is transactivated by diverse cellular signal transduction pathways. We and others have shown that the P3 promoter in ATLL cells is regulated by the ETS signaling pathway [45, 46] and, recently, we have shown that the P2 promoter is regulated by the NF-κB pathway . Our data in this investigation demonstrated that PTHrP was up-regulated during immortalization through both the P2 and P3 promoters. The ratio of the P2/P3 promoter-initiated transcripts during the immortalization phase was higher (1:2) than in human HTLV-1-transformed T-cells (MT-2; 1:4) or ATLL cells (data not presented) . NF-κB is known to play an important role during the immortalization process and our data showed that the P2 promoter was highly expressed during immortalization. This suggests that NF-κB activity was responsible for transactivating the PTHrP P2 promoter during immortalization.
HTLV-1 tax has been shown to transactivate PTHrP. However, ATLL cells with no significant Tax expression have very high levels of PTHrP. Recently, we have shown that Tax mRNA expression was inversely proportional to PTHrP mRNA expression and PTHrP can be regulated in a Tax-independent manner in ATLL cells . To investigate possible mechanisms for up-regulation of PTHrP in our co-culture assays, we measured the expression of Tax/Rex mRNA. Our data showed that there was no correlation between PTHrP and Tax/Rex mRNA expression. Therefore, induction of PTHrP could either be due to an indirect effect of Tax or possibly a Tax-independent mechanism.
Data from the transfection experiments showed that HTLV-1 infection up-regulated PTHrP expression mildly and suggested that additional cellular events were required to induce the high level PTHrP expression seen in ATLL cells. Alternatively, PTHrP expression might be dependent on cell-type and require lymphocyte-specific factors for marked up-regulation. Over-expression of Rex alone resulted in the up-regulation of PTHrP. Interestingly, Rex and PTHrP have a similar nuclear transport signal and can bind to CRM1 [39, 48]. Therefore, the increased expression of PTHrP in the presence of Rex may have been due to increased nuclear export of PTHrP or alternatively due to increased PTHrP mRNA stability since Rex increases the mRNA stability of some genes, such as IL-2Rα .
We analyzed the expression of MIP-1α, a second cellular gene that is known to play an important role in the pathogenesis of HHM, in the co-cultures. The data showed that MIP-1α was markedly up-regulated as early as 1 week following HTLV-1 infection of PBMCs. These data are in agreement with reports that showed MIP-1α was up-regulated during activation of T-lymphocytes . Our data demonstrated that MIP-1α was up-regulated early in the co-cultures with HTLV-1 infection due to activation of T-lymphocytes. In contrast, up-regulation of PTHrP occurred later during the immortalization, which supported a specific role for PTHrP in the transformation process.
Our data demonstrated that PTHrP was dramatically and specifically up-regulated during the immortalization of PBMCs with HTLV-1 in a Tax-independent manner. PTHrP likely functioned in an autocrine manner with the PTH1R facilitating the transformation process. Although further investigations are required to understand the role of PTHrP in the transformation process, it is apparent that PTHrP is up-regulated not only during HHM but also during early HTLV-1 infection implicating an important dual role for PTHrP in the pathogenesis of ATLL. Novel therapies directed against PTHrP will be an important strategy to prevent ATLL in HTLV-1-infected patients.
Materials and methods
293T cells were maintained in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM glutamine, penicillin (100 U/mL), and streptomycin (100 μg/mL). PBMCs were cultured in RPMI 1640 medium supplemented with 20% FBS, 2 mM glutamine, and antibiotics in the presence or absence of 10 U/mL IL-2 (Boehringer Mannheim, Mannheim, Germany).
Long-term co-culture assays
PBMCs were isolated from the blood of healthy donors by centrifugation over Ficoll-Paque (Pharmacia, Piscataway, NJ). Long term co-culture assays were performed as described previously . Briefly, 2 × 106 PBMCs were cultured alone or co-cultured with 106 SLB-1 producer cells (in approximately 2 mL of culture medium) irradiated with 10,000 rad in 24-well culture plates in the absence (PBMC-1, 2 + HTLV-1; PBMC-1, 2 represent PBMCs from two different donors) or presence of 10 U/mL human IL-2 (hIL-2) (PBMC-1, 2, 3 + HTLV-1+ IL-2; PBMC-1, 2, 3 represent PBMCs from three different donors). Viable cells were counted weekly by trypan blue exclusion. Cells that continued to produce p19 Gag antigen and proliferate 12 weeks after co-culture were identified as HTLV-1-immortalized. PBMCs cultured alone (PBMC-1, PBMC-2) or the in the presence of IL-2 (PBMC-1 + IL-2, PBMC-2 + IL-2) or phytohemagglutinin (PHA) (PBMC-1+PHA, PBMC-2 + PHA) without HTLV-1 infection were used as controls.
Real time RT-PCR
Total RNA was extracted using TRIZOL® Reagent (Invitrogen, Carlsbad, CA). To measure the total PTHrP mRNA, 1 μg RNA was reverse-transcribed and amplified by real-time RT-PCR analysis using TaqMan® Gene Expression assays (4331182, Applied Biosystems, CA). β2M (4333766, Applied Biosystems) was used as a reference gene. PTHrP P2 and P3 promoter-initiated transcripts, PTH1R and HTLV-1 Tax mRNAs were measured as described previously [38, 52, 53]. The PTH1R gels were scanned with a Typhoon 9410 Variable Mode Imager (GE Healthcare Bio-Sciences Corp.) and PTH1R PCR products were quantified using ImageQuant TL Version 7.0 software.
PTHrP Immunoradiometric Assay
PTHrP concentrations were measured in the conditioned medium using a two-site immunoradiometric assay (DSL, Webster, TX) specific for the PTHrP N-terminal region (amino acids 1 to 40) and mid-region (amino acids 57 to 80).
Enzyme Linked Immunosorbant Assays
p19 Gag protein in the culture supernatant was measured using a commercially available ELISA kit (Zeptometrix, Buffalo, NY). MIP-1α protein in the conditioned medium was measured using the Quantikine Human CCL3/MIP-1α Immunoassay (R&D systems, Minneapolis, MN).
Plasmids and transfections
The PTHrP P2/P3 luciferase construct was made by cloning the PTHrP P2/P3 promoter fragment (-1120 Bam H1 to +1 Hind III) into the pGL2 basic vector. ACH, pcTax, BCRex, HBZ plasmids were obtained from the laboratory of Dr. Patrick Green (The Ohio State University). p12, p13 and p30 expression plasmids were obtained from laboratory of Dr. Michael Lairmore (The Ohio State University). 293T cells were transfected with either PTHrP P2/P3 PGL2 Luc plasmid alone or with ACH, pcTax, BCRex, HBZ, p12, p13, p30 vectors. pcDNA-3.1 was used as a "filler" plasmid so that the total amount of DNA would be the same in all transfection groups. The plasmid pβgal-Control Vector (250 ng) was included in each transfection and served as an internal control to correct for transfection efficiency. Luciferase activity was measured with the Luciferase Assay System (Promega) using 40 μl of lysate. Simultaneously, β-galactosidase activity was measured with the Luminescent β-Galactosidase Detection Kit II (BD Biosciences).
For the co-culture experiments, linear mixed models with repeated measures (ANOVA with repeated measures) were used to study the effects of time, treatment and the interaction between time and treatment. The square-root transformation was used for cell number and MIP-1α data to achieve normality and homogeneous variances. Dunnett's method was used to adjust for multiple comparisons versus the control group. In some treatments (PBMC, PBMC+IL2, PBMC+PHA), cell numbers and protein level were zero after 6 weeks. Thus, a non-parametric method (Wilcoxon sum rank) was used for the comparison among non-zero groups to the zero groups after week 6. ANOVA with Dunnett's tests were used to analyze the data from transfection experiments and PTH1R RT-PCR quantification. A multiplicity-adjusted p value less than alpha = 0.05 was considered significant. In the figures, either raw data or averages were plotted to improve readability and visualization of the data.
This work was supported by the National Cancer Institute (CA100730 and CA77911). MVPN was supported by the Glenn C Barber Fellowship from the College of Veterinary Medicine, The Ohio State University; TR and SS were supported by the National Center for Research Resources (RR00168) and the NCRR T32 (RR07073), respectively.
- Osame M, Arimura K, Nakagawa M, Umehara F, Usuku K, Ijichi S: HTLV-I associated myelopathy (HAM): review and recent studies. Leukemia. 1997, 11 (Suppl 3): 63-64.PubMedGoogle Scholar
- 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 USA. 1980, 77: 7415-7419. 10.1073/pnas.77.12.7415.PubMed CentralView ArticlePubMedGoogle Scholar
- Edlich RF, Arnette JA, Williams FM: Global epidemic of human T-cell lymphotropic virus type-I (HTLV-I). J Emerg Med. 2000, 18: 109-119. 10.1016/S0736-4679(99)00173-0.View ArticlePubMedGoogle Scholar
- Bangham CR: Human T-lymphotropic virus type 1 (HTLV-1): persistence and immune control. Int J Hematol. 2003, 78: 297-303.View ArticlePubMedGoogle Scholar
- Igakura T, Stinchcombe JC, Goon PK, Taylor GP, Weber JN, Griffiths GM, et al: Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science. 2003, 299: 1713-1716. 10.1126/science.1080115.View ArticlePubMedGoogle Scholar
- Arisawa K, Soda M, Endo S, Kurokawa K, Katamine S, Shimokawa I, et al: Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer. 2000, 85: 319-324. 10.1002/(SICI)1097-0215(20000201)85:3<319::AID-IJC4>3.0.CO;2-B.View ArticlePubMedGoogle Scholar
- Matsuoka M, Jeang KT: Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer. 2007, 7: 270-280. 10.1038/nrc2111.View ArticlePubMedGoogle Scholar
- Yasunaga J, Matsuoka M: Human T-cell leukemia virus type I induces adult T-cell leukemia: from clinical aspects to molecular mechanisms. Cancer Control. 2007, 14: 133-140.PubMedGoogle Scholar
- 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 USA. 1987, 84: 5389-5393. 10.1073/pnas.84.15.5389.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1126/science.2843985.View ArticlePubMedGoogle Scholar
- Ressler S, Morris GF, Marriott SJ: Human T-cell leukemia virus type 1 Tax transactivates the human proliferating cell nuclear antigen promoter. J Virol. 1997, 71: 1181-1190.PubMed CentralPubMedGoogle Scholar
- Fujii M, Sassone-Corsi P, Verma IM: c-fos promoter trans-activation by the tax1 protein of human T-cell leukemia virus type I. Proc Natl Acad Sci USA. 1988, 85: 8526-8530. 10.1073/pnas.85.22.8526.PubMed CentralView ArticlePubMedGoogle Scholar
- Ratner L: Regulation of expression of the c-sis proto-oncogene. Nucleic Acids Res. 1989, 17: 4101-4115. 10.1093/nar/17.11.4101.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1038/sj.onc.1208976.View ArticlePubMedGoogle Scholar
- Younis I, Green PL: The human T-cell leukemia virus Rex protein. Front Biosci. 2005, 10: 431-445. 10.2741/1539.PubMed CentralView ArticlePubMedGoogle Scholar
- Ye J, Silverman L, Lairmore MD, Green PL: HTLV-1 Rex is required for viral spread and persistence in vivo but is dispensable for cellular immortalization in vitro. Blood. 2003, 102: 3963-3969. 10.1182/blood-2003-05-1490.PubMed CentralView ArticlePubMedGoogle Scholar
- Albrecht B, Lairmore MD: Critical role of human T-lymphotropic virus type 1 accessory proteins in viral replication and pathogenesis. Microbiol Mol Biol Rev. 2002, 66: 396-406. 10.1128/MMBR.66.3.396-406.2002.PubMed CentralView ArticlePubMedGoogle Scholar
- Arnold J, Yamamoto B, Li M, Phipps AJ, Younis I, Lairmore MD, et al: Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1. Blood. 2006, 107: 3976-3982. 10.1182/blood-2005-11-4551.PubMed CentralView ArticlePubMedGoogle Scholar
- Kiyokawa T, Yamaguchi K, Takeya M, Takahashi K, Watanabe T, Matsumoto T, et al: Hypercalcemia and osteoclast proliferation in adult T-cell leukemia. Cancer. 1987, 59: 1187-1191. 10.1002/1097-0142(19870315)59:6<1187::AID-CNCR2820590626>3.0.CO;2-8.View ArticlePubMedGoogle Scholar
- Niitsu Y, Urushizaki Y, Koshida Y, Terui K, Mahara K, Kohgo Y, et al: Expression of TGF-beta gene in adult T cell leukemia. Blood. 1988, 71: 263-266.PubMedGoogle Scholar
- Nosaka K, Miyamoto T, Sakai T, Mitsuya H, Suda T, Matsuoka M: Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor kappaB ligand on adult T-cell leukemia cells. Blood. 2002, 99: 634-640. 10.1182/blood.V99.2.634.View ArticlePubMedGoogle Scholar
- Okada Y, Tsukada J, Nakano K, Tonai S, Mine S, Tanaka Y: Macrophage inflammatory protein-1alpha induces hypercalcemia in adult T-cell leukemia. J Bone Miner Res. 2004, 19: 1105-1111. 10.1359/JBMR.040314.View ArticlePubMedGoogle Scholar
- Senba M, Kawai K: Hypercalcemia and production of parathyroid hormone-like protein in adult T-cell leukemia-lymphoma. Eur J Haematol. 1992, 48: 278-279.View ArticlePubMedGoogle Scholar
- Wano Y, Hattori T, Matsuoka M, Takatsuki K, Chua AO, Gubler U, et al: Interleukin 1 gene expression in adult T cell leukemia. J Clin Invest. 1987, 80: 911-916. 10.1172/JCI113152.PubMed CentralView ArticlePubMedGoogle Scholar
- Prager D, Rosenblatt JD, Ejima E: Hypercalcemia, parathyroid hormone-related protein expression and human T-cell leukemia virus infection. Leuk Lymphoma. 1994, 14: 395-400. 10.3109/10428199409049695.View ArticlePubMedGoogle Scholar
- Watanabe T, Yamaguchi K, Takatsuki K, Osame M, Yoshida M: Constitutive expression of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-1) carriers and adult T cell leukemia patients that can be trans-activated by HTLV-1 tax gene. J Exp Med. 1990, 172: 759-765. 10.1084/jem.172.3.759.View ArticlePubMedGoogle Scholar
- Wake A, Tanaka Y, Nakatsuka K, Misago M, Oda S, Morimoto I, et al: Calcium-dependent homotypic adhesion through leukocyte function-associated antigen-1/intracellular adhesion molecule-1 induces interleukin-1 and parathyroid hormone-related protein production on adult T-cell leukemia cells in vitro. Blood. 1995, 86: 2257-2267.PubMedGoogle Scholar
- Dunbar ME, Wysolmerski JJ, Broadus AE: Parathyroid hormone-related protein: from hypercalcemia of malignancy to developmental regulatory molecule. Am J Med Sci. 1996, 312: 287-294. 10.1097/00000441-199612000-00007.View ArticlePubMedGoogle Scholar
- Gessi M, Monego G, Calviello G, Lanza P, Giangaspero F, Silvestrini A, et al: Human parathyroid hormone-related protein and human parathyroid hormone receptor type 1 are expressed in human medulloblastomas and regulate cell proliferation and apoptosis in medulloblastoma-derived cell lines. Acta Neuropathol. 2007, 114: 135-145. 10.1007/s00401-007-0212-y.View ArticlePubMedGoogle Scholar
- Wysolmerski JJ, Stewart AF: The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor. Annu Rev Physiol. 1998, 60: 431-460. 10.1146/annurev.physiol.60.1.431.View ArticlePubMedGoogle Scholar
- Franzese O, Balestrieri E, Comandini A, Forte G, Macchi B, Bonmassar E: Telomerase activity of human peripheral blood mononuclear cells in the course of HTLV type 1 infection in vitro. AIDS Res Hum Retroviruses. 2002, 18: 249-251. 10.1089/088922202753472810.View ArticlePubMedGoogle Scholar
- Richard V, Rosol TJ, Foley J: PTHrP gene expression in cancer: do all paths lead to Ets?. Crit Rev Eukaryot Gene Expr. 2005, 15: 115-132. 10.1615/CritRevEukaryotGeneExpr.v15.i2.30.PubMed CentralView ArticlePubMedGoogle Scholar
- Martin TJ, Moseley JM, Williams ED: Parathyroid hormone-related protein: hormone and cytokine. J Endocrinol. 1997, 154 (Suppl): S23-S37.PubMedGoogle Scholar
- Philbrick WM, Wysolmerski JJ, Galbraith S, Holt E, Orloff JJ, Yang KH, et al: Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev. 1996, 76: 127-173.PubMedGoogle Scholar
- Richard V, Lairmore MD, Green PL, Feuer G, Erbe RS, Albrecht B, et al: 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 CentralView ArticlePubMedGoogle Scholar
- Menten P, Wuyts A, Van Damme J: Macrophage inflammatory protein-1. Cytokine Growth Factor Rev. 2002, 13: 455-481. 10.1016/S1359-6101(02)00045-X.View ArticlePubMedGoogle Scholar
- Sharma V, Lorey SL: Autocrine role of macrophage inflammatory protein-1 beta in human T-cell lymphotropic virus type-I tax-transfected Jurkat T-cells. Biochem Biophys Res Commun. 2001, 287: 910-913. 10.1006/bbrc.2001.5671.View ArticlePubMedGoogle Scholar
- Li M, Green PL: Detection and quantitation of HTLV-1 and HTLV-2 mRNA species by real-time RT-PCR. J Virol Methods. 2007, 142: 159-168. 10.1016/j.jviromet.2007.01.023.PubMed CentralView ArticlePubMedGoogle Scholar
- Lam MH, Thomas RJ, Martin TJ, Gillespie MT, Jans DA: Nuclear and nucleolar localization of parathyroid hormone-related protein. Immunol Cell Biol. 2000, 78: 395-402. 10.1046/j.1440-1711.2000.00919.x.View ArticlePubMedGoogle Scholar
- Motokura T, Endo K, Kumaki K, Ogata E, Ikeda K: Neoplastic transformation of normal rat embryo fibroblasts by a mutated p53 and an activated ras oncogene induces parathyroid hormone-related peptide gene expression and causes hypercalcemia in nude mice. J Biol Chem. 1995, 270: 30857-30861. 10.1074/jbc.270.52.30857.View ArticlePubMedGoogle Scholar
- Insogna KL, Stewart AF, Morris CA, Hough LM, Milstone LM, Centrella M: Native and a synthetic analogue of the malignancy-associated parathyroid hormone-like protein have in vitro transforming growth factor-like properties. J Clin Invest. 1989, 83: 1057-1060. 10.1172/JCI113947.PubMed CentralView ArticlePubMedGoogle Scholar
- 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 CentralView ArticlePubMedGoogle Scholar
- Clemens TL, Cormier S, Eichinger A, Endlich K, Fiaschi-Taesch N, Fischer E, et al: Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets. Br J Pharmacol. 2001, 134: 1113-1136. 10.1038/sj.bjp.0704378.PubMed CentralView ArticlePubMedGoogle Scholar
- Sourbier C, Massfelder T: Parathyroid hormone-related protein in human renal cell carcinoma. Cancer Lett. 2006, 240: 170-182. 10.1016/j.canlet.2005.08.020.View ArticlePubMedGoogle Scholar
- 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. 10.1074/jbc.272.8.4953.View ArticlePubMedGoogle Scholar
- Richard V, Nadella MV, Green PL, Lairmore MD, Feuer G, Foley JG, et al: Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma. Leukemia. 2005, 19: 1175-1183. 10.1038/sj.leu.2403787.PubMed CentralView ArticlePubMedGoogle Scholar
- Nadella MV, Dirksen WP, Nadella KS, Shu S, Cheng AS, Morgenstern JA, et al: Transcriptional regulation of parathyroid hormone-related protein promoter P2 by NF-kappaB in adult T-cell leukemia/lymphoma. Leukemia. 2007, 21: 1752-1762. 10.1038/sj.leu.2404798.PubMed CentralView ArticlePubMedGoogle Scholar
- Cingolani G, Bednenko J, Gillespie MT, Gerace L: Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta. Mol Cell. 2002, 10: 1345-1353. 10.1016/S1097-2765(02)00727-X.View ArticlePubMedGoogle Scholar
- Kanamori H, Suzuki N, Siomi H, Nosaka T, Sato A, Sabe H, et al: HTLV-1 p27rex stabilizes human interleukin-2 receptor alpha chain mRNA. EMBO J. 1990, 9: 4161-4166.PubMed CentralPubMedGoogle Scholar
- Sharma V, May CC: Human T-cell lymphotrophic virus type-I tax gene induces secretion of human macrophage inflammatory protein-1alpha. Biochem Biophys Res Commun. 1999, 262: 429-432. 10.1006/bbrc.1999.1242.View ArticlePubMedGoogle Scholar
- 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. 10.1182/blood-2005-03-1333.PubMed CentralView ArticlePubMedGoogle Scholar
- Richard V, Luchin A, Brena RM, Plass C, Rosol TJ: Quantitative evaluation of alternative promoter usage and 3' splice variants for parathyroid hormone-related protein by real-time reverse transcription-PCR. Clin Chem. 2003, 49: 1398-1402. 10.1373/49.8.1398.View ArticlePubMedGoogle Scholar
- Southby J, O'Keeffe LM, Martin TJ, Gillespie MT: Alternative promoter usage and mRNA splicing pathways for parathyroid hormone-related protein in normal tissues and tumours. Br J Cancer. 1995, 72: 702-707.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.