Life, Death, and Tax: Role of HTLV-I Oncoprotein in Genetic Instability and Cellular Transformation

Human T-cell leukemia virus type I (HTLV-I) 1The abbreviations used are: HTLV-I, human T-cell leukemia virus type I; ATL, adult T-cell leukemia; LTR, long terminal repeat; IL, interleukin; CDK, cyclin-dependent kinase; BER, base excision repair; NER, nucleotide excision repair; PCNA, proliferating cell nuclear antigen; MSC, mitotic spindle assembly checkpoint; AML, acute myeloid leukemia. causes adult T-cell leukemia (ATL) (1Poiesz B.J. Ruscetti F.W. Gadzar A.F. Bunn P.A. Minna J.D. Gallo R.C. Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 7415-7419Google Scholar, 2Hinuma Y. Nagata K. Misoka M. Nakai T. Matsumoto T. Kiroshita K. Shirakwa S. Miyoshi I. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 6476-6480Google Scholar, 3Matsuoka M. Oncogene. 2003; 22: 5131-5140Google Scholar). The virus is also associated with a neuropathy/myelopathy termed HTLV-associated myelopathy and tropical spastic paraparesis. ATL develops in 2–5% of HTLV-I-infected individuals after a long latent period, suggesting a multistage process of immortalization and transformation of T-lymphocytes. Extant data suggest that 8 discrete events likely occur serially in vivo before an HTLV-I-infected cell becomes immortalized and transformed (4Okamoto T. Ohno Y. Tsugane S. Watanabe S. Shimoyama M. Tajima K. Miwa M. Shimotohno K. Jpn. J. Cancer Res. 1989; 80: 191-195Google Scholar). How HTLV-I infection progresses from clinical latency to T-cell malignancy is not well understood but involves the unique viral transactivator/oncoprotein, Tax (Fig. 1). Tax has been shown to be singly sufficient for immortalizing T-lymphocytes (5Grassmann R. Dengler C. Muller-Fleckenstein I. McGuire K. Dokhelar M.C. Sodroski J.G. Haseltine W.A. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3351-3355Google Scholar, 6Ross T.M. Pettiford S.M. Green P.L. J. Virol. 1996; 70: 5194-5202Google Scholar) and transforming rat fibroblasts (7Tanaka A. Takahashi G. Yamaoka S. Nosaka T. Maki M. Hatanaka M. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 1071-1075Google Scholar). Further, transgenic mice expressing Tax (driven by the HTLV-I long terminal repeat (LTR)) develop neurofibroma, a tumor of mesenchymal tissue (8Nerenberg M. Hinrichs S.H. Reynolds R.K. Khoury G. Jay G. Science. 1987; 237: 1324-1329Google Scholar). Finally, large granular lymphocytic leukemia has been found in mice transgenic for Tax expressed from the T-cell specific, granzyme B promoter (9Grossman W.J. Kimata J.T. Wong F.H. Zutter M. Ley T.J. Ratner L. Proc. Natl. Acad. Sci. U. S. A. 1995; 14: 1057-1061Google Scholar). It is estimated that cells in the human body divide 1016 times during a lifetime. To control and prevent errors in cell divisions, mammalian cells have evolved “gatekeepers” and “caretakers” to regulate the rate of cell growth and the fidelity by which cellular genetic information is transmitted to progenies (10Kinzler K.W. Vogelstein B. Cell. 1996; 87: 159-170Google Scholar). Gatekeepers monitor the net proliferative capacity of a cell, whereas caretakers act to eliminate DNA damages. Accordingly, one perspective is that transformation occurs when both gatekeeper and caretaker functions are abrogated. Using HTLV-I as a model, we review in a non-exhaustive fashion current thoughts on how Tax perturbs normal cellular regulation and engenders cellular transformation. HTLV-I belongs to the Deltaretrovirus genera of the Orthoretrovirinae family. In vivo, the virus has a tropism for CD4+ T-cells (11Richardson J.H. Edwards A.J. Cruickshank J.K. Rudge P. Dalgleish A.G. J. Virol. 1990; 64: 5682-5687Google Scholar) although CD8+ T-cells may also serve as a reservoir (12Nagai M. Brennan M.B. Sakai J.A. Mora C.A. Jacobson S. Blood. 2001; 98: 1858-1861Google Scholar). HTLV-I infection is primarily transmitted via cell-cell contact (13Okochi K. Sato H. Princess Takamatsu Symp. 1984; 15: 129-135Google Scholar, 14Igakura T. Stinchcombe J.C. Goon P.K. Taylor G.P. Weber J.N. Griffiths G.M. Tanaka Y. Osame M. Bangham C.R. Science. 2003; 299: 1713-1716Google Scholar). Recently, the human Glut1 glucose transporter has been identified as a receptor for infection by cell-free virus (15Manel N. Kim F.J. Kinet S. Taylor N. Sitbon M. Battini J.L. Cell. 2003; 115: 449-459Google Scholar). The proviral genome of HTLV-I is roughly 9 kbp, and like other retroviruses, contains two LTRs flanking structural genes encoding Gag, Pol, and Env (Fig. 1). An additional region located between env and the 3′-LTR, known as the pX region, encodes accessory proteins. The pX region has four partially overlapping reading frames (ORF, Fig. 1), of which ORF IV encodes Tax. Tax is predominantly a nuclear phosphoprotein (16Semmes O.J. Jeang K.T. J. Virol. 1996; 70: 6347-6357Google Scholar), which can shuttle into the cytoplasm using a nuclear export signal (17Burton M. Upadhyaya C.D. Maier B. Hope T.J. Semmes O.J. J. Virol. 2000; 74: 2351-2364Google Scholar). The mechanism of this shuttling is unclear; however, recent findings that Tax binds tristetrapolin (18Twizere J.C. Kruys V. Lefebvre L. Vanderplasschen A. Collete D. Debacq C. Lai W.S. Jauniaux J.C. Bernstein L.R. Semmes O.J. Burny A. Blackshear P.J. Kettmann R. Willems L. J. Natl. Cancer Inst. 2003; 95: 1846-1859Google Scholar) and that tristetrapolin associates with nucleoporin Nup214 (19Carman J.A. Nadler S.G. Biochem. Biophys. Res. Commun. 2004; 315: 445-449Google Scholar) raise the possibility that tristetrapolin may serve as a possible nucleocytoplasmic transporter for Tax. Nevertheless, the primary nuclear activity of Tax is to modulate transcription from the HTLV-I LTR (20Seiki M. Inoue J. Takeda T. Yoshida M. EMBO J. 1986; 5: 561-565Google Scholar, 21Brady J. Jeang K.T. Duvall J. Khoury G. J. Virol. 1987; 61: 2175-2181Google Scholar, 22Jeang K.T. Boros I. Brady J. Radonovich M. Khoury G. J. 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Princler G.L. Shimozato O. Taylor G.P. Bangham C.R. Derse D. Blood. 2003; 102: 4130-4136Google Scholar) among others. Indeed the breadth of Tax's transcriptional reprogramming of host cell genes was verified by DNA array studies which showed that of 2000 assayed genes the expression profiles of ∼300 were significantly altered (31Ng P.W. Iha H. Iwanaga Y. Bittner M. Chen Y. Jiang Y. Gooden G. Trent J.M. Meltzer P. Jeang K.T. Zeichner S.L. Oncogene. 2001; 20: 4484-4496Google Scholar). Tax influences so many promoters through its capacity to act in four discrete signaling pathways: CREB/ATF (reviewed in Ref. 32Mesnard J.M. Devaux C. Virology. 1999; 257: 277-284Google Scholar); NF-κB (reviewed in Ref. 33Sun S.C. Ballard D.W. Oncogene. 1999; 18: 6948-6958Google Scholar); AP-1 (34Jeang K.T. Chiu R. Santos E. Kim S.J. Virology. 1991; 181: 218-227Google Scholar); and SRF (35Fujii M. Tsuchiya J. Chuhjo T. Akizawa T. Seiki M. Genes Dev. 1992; 6: 2066-2076Google Scholar). 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Genes Dev. 1999; 13: 1501-1512Google Scholar). An important cell cycle control resides at the transition from G1 to S, which is substantially governed by the retinoblastoma tumor suppressor (Rb) (42Matsushime H. Quelle D.E. Shurtleff S.A. Shibuya M. Sherr C.J. Kato J.Y. Mol. Cell. Biol. 1994; 14: 2066-2076Google Scholar, 43Resnitzky D. Gossen M. Bujard H. Reed S.I. Mol. Cell. Biol. 1994; 14: 1669-1679Google Scholar). At this juncture, D- and E-cyclins with partner CDKs (reviewed in Refs. 40Hunter T. Pines J. Cell. 1994; 79: 573-582Google Scholar, 41Sherr C.J. Roberts J.M. Genes Dev. 1999; 13: 1501-1512Google Scholar, and 44Sherr C.J. Cell. 1994; 79: 551-555Google Scholar) converge to phosphorylate Rb. Hypophosphorylated Rb sequesters and inactivates E2F factors, which are needed for the expression of genes (such as dihydrofolate reductase, DNA polymerase α, and cyclins) that are critical for S phase events (reviewed in Ref. 45Grana X. Reddy E.P. 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Blood. 1998; Scholar). not a between the two is that one (ATL) function through viral whereas the other so through physical of (i.e. of the for in ATL The to be one that of can the of by cells, but studies suggest that Tax directly errors in two Tax can the of and likely through the of the B. I. T. J. Mol. Cell. Biol. 2003; Scholar), to like the human virus S. Munger K. Crit. Rev. Eukaryotic Gene Expression. 2003; 13: 9-23Google Scholar), Tax can also in and K. T. in which is mechanism for D. Rev. Mol. Cell. Biol. 2004; 5: Scholar). Finally, is a of that as the of D. Rev. Mol. Cell. Biol. 2004; 5: Scholar). to this we that Tax expression (i.e. cells T. Y. Hinrichs S.H. J. Virol. Scholar, F. Jeang K.T. Cell. 1998; Scholar). to this the that Tax can and Rb C. K.G. F. I. F. R. Jeang K.T. Mol. Cell. Biol. 1998; 18: Scholar, C.A. Radonovich M. J. Kim S.J. Brady J.N. J. Virol. 1998; Scholar, T. Ono H. N. Shimotohno K. 1997; Scholar, S. R. A. C. T. L. Waldmann T. G. G. 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S.J. Oncogene. 2000; Scholar, T. Jeang K.T. 2004; Scholar). the between and is influenced by the cellular cell type genetic and multiple signaling on which of genes that Tax activates (31Ng P.W. Iha H. Iwanaga Y. Bittner M. Chen Y. Jiang Y. Gooden G. Trent J.M. Meltzer P. Jeang K.T. Zeichner S.L. Oncogene. 2001; 20: 4484-4496Google Scholar) which of that Tax binds K. M.E. Fuente C. L. A. S. H. A. A. F. J. Biol. 2004; Scholar) the normal cellular (i.e. be (i.e. by of factors in to Tax that this for HTLV-I-infected T-cells be a for individuals are with It is estimated that 2–5% of develop ATL lifetime. The and of HTLV-I have mechanistic into ATL transformation. Using Tax as a we have that viral for transformation mechanistic in of events to be genetic by by of cellular and of into the and for the of that growth the process is and the and to this for for critical reading of the and for of and