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Science 11 September 1987:
Vol. 237. no. 4820, pp. 1324 - 1329
DOI: 10.1126/science.2888190
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Articles

Science, Vol 237, Issue 4820, 1324-1329
Copyright © 1987 by American Association for the Advancement of Science

articles

The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice

M Nerenberg, SH Hinrichs, RK Reynolds, G Khoury, and G Jay

Human T-lymphotropic virus type 1 (HTLV-1) is a suspected causative agent of adult T-cell leukemia. One of the viral genes encodes a protein (tat) that not only results in transactivation of viral gene expression but may also regulate the expression of certain cellular genes that are important for cell growth. Transgenic mice that expressed the authentic tat protein under the control of the HTLV-1 long terminal repeat were generated, and cell types that are permissive for the viral promoter and the effects of the tat gene on these cells were studied. Three of eight founder mice with high levels of expression of the transgene in muscle were bred and then analyzed. All developed soft tissue tumors at multiple sites between 13 to 17 weeks of age. This phenotype was transmitted to nine of nine offspring that inherited the tat gene and were available for analysis. The remaining five founders expressed the transgene in the thymus, as well as in muscle. This second group of mice all exhibited extensive thymic depletion and growth retardation; in all of these mice, death occurred between 3 to 6 weeks of age before tumors became macroscopically visible. The tat gene under the control of the HTLV-1 regulatory region showed tissue-specific expression and the tat protein efficiently induced mesenchymal tumors. The data establish tat as an oncogenic protein and HTLV-1 as a transforming virus.


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J. Virol. 80, 10036-10044
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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.
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Lethal Cutaneous Disease in Transgenic Mice Conditionally Expressing Type I Human T Cell Leukemia Virus Tax.
H. Kwon, L. Ogle, B. Benitez, J. Bohuslav, M. Montano, D. W. Felsher, and W. C. Greene (2005)
J. Biol. Chem. 280, 35713-35722
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Evidence for NF-{kappa}B- and CBP-Independent Repression of p53's Transcriptional Activity by Human T-Cell Leukemia Virus Type 1 Tax in Mouse Embryo and Primary Human Fibroblasts.
A. Miyazato, S. Sheleg, H. Iha, Y. Li, and K.-T. Jeang (2005)
J. Virol. 79, 9346-9350
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Resistance to Apo2 Ligand (Apo2L)/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Apoptosis and Constitutive Expression of Apo2L/TRAIL in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines.
T. Matsuda, A. Almasan, M. Tomita, J.-n. Uchihara, M. Masuda, K. Ohshiro, N. Takasu, H. Yagita, T. Ohta, and N. Mori (2005)
J. Virol. 79, 1367-1378
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Ubiquitination of Human T-Cell Leukemia Virus Type 1 Tax Modulates Its Activity.
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Transcriptional activation of immediate-early gene ETR101 by human T-cell leukaemia virus type I Tax.
L. Chen, S. Ma, B. Li, T. Fink, V. Zachar, M. Takahashi, J. Cuttichia, L.-C. Tsui, P. Ebbesen, and X. Liu (2003)
J. Gen. Virol. 84, 3203-3214
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Functional Domain Structure of Human T-Cell Leukemia Virus Type 2 Rex.
M. Narayan, I. Younis, D. M. D'Agostino, and P. L. Green (2003)
J. Virol. 77, 12829-12840
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HTLV-1 Rex is required for viral spread and persistence in vivo but is dispensable for cellular immortalization in vitro.
J. Ye, L. Silverman, M. D. Lairmore, and P. L. Green (2003)
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Human T-Lymphotropic Virus Type 1 Oncoprotein Tax Promotes Unscheduled Degradation of Pds1p/Securin and Clb2p/Cyclin B1 and Causes Chromosomal Instability.
B. Liu, M.-H. Liang, Y.-l. Kuo, W. Liao, I. Boros, T. Kleinberger, J. Blancato, and C.-Z. Giam (2003)
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Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2.
J. Ye, L. Xie, and P. L. Green (2003)
J. Virol. 77, 7728-7735
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Of mice and models: improved animal models for biomedical research.
E. Bockamp, M. Maringer, C. Spangenberg, S. Fees, S. Fraser, L. Eshkind, F. Oesch, and B. Zabel (2002)
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Differential Requirements for Activation of Integrated and Transiently Transfected Human T-Cell Leukemia Virus Type 1 Long Terminal Repeat.
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J. Virol. 76, 12564-12573
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Human T-Lymphotropic Virus Type 1 Oncoprotein Tax Promotes S-Phase Entry but Blocks Mitosis.
M.-H. Liang, T. Geisbert, Y. Yao, S. H. Hinrichs, and C.-Z. Giam (2002)
J. Virol. 76, 4022-4033
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Mutant Tax Protein from Bovine Leukemia Virus with Enhanced Ability To Activate the Expression of c-fos.
S. Tajima and Y. Aida (2002)
J. Virol. 76, 2557-2562
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Human T-Cell Leukemia Virus Type 2 (HTLV-2) Tax Protein Transforms a Rat Fibroblast Cell Line but Less Efficiently than HTLV-1 Tax.
K. Endo, A. Hirata, K. Iwai, M. Sakurai, M. Fukushi, M. Oie, M. Higuchi, W. W. Hall, F. Gejyo, and M. Fujii (2002)
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Human T-Cell Leukemia Virus Type 1 Tax Protein Inhibits the Expression of the Basic Helix-Loop-Helix Transcription Factor MyoD in Muscle Cells: Maintenance of Proliferation and Repression of Differentiation.
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Cell Growth Differ. 12, 613-622
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Retrovirus-Induced Ovine Pulmonary Adenocarcinoma, an Animal Model for Lung Cancer.
M. Palmarini and H. Fan (2001)
J Natl Cancer Inst 93, 1603-1614
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Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor {beta} signaling through interaction with CREB-binding protein/p300.
N. Mori, M. Morishita, T. Tsukazaki, C.-Z. Giam, A. Kumatori, Y. Tanaka, and N. Yamamoto (2001)
Blood 97, 2137-2144
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CREB/ATF-Dependent Repression of Cyclin A by Human T-Cell Leukemia Virus Type 1 Tax Protein.
K. V. Kibler and K.-T. Jeang (2001)
J. Virol. 75, 2161-2173
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Reciprocal Interactions between Human T-Lymphotropic Virus Type 1 and Prostaglandins: Implications for Viral Transmission.
M. Moriuchi, H. Inoue, and H. Moriuchi (2001)
J. Virol. 75, 192-198
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Genetic Evidence of a Role for ATM in Functional Interaction between Human T-Cell Leukemia Virus Type 1 Tax and p53.
P. L. Van, K.-W. Yim, D.-Y. Jin, G. Dapolito, A. Kurimasa, and K.-T. Jeang (2001)
J. Virol. 75, 396-407
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Discordance between Bovine Leukemia Virus Tax Immortalization In Vitro and Oncogenicity In Vivo.
J.-C. Twizere, P. Kerkhofs, A. Burny, D. Portetelle, R. Kettmann, and L. Willems (2000)
J. Virol. 74, 9895-9902
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Cell Type-specific E2F Activation and Cell Cycle Progression Induced by the Oncogene Product Tax of Human T-cell Leukemia Virus Type I.
K. Ohtani, R. Iwanaga, M. Arai, Y. Huang, Y. Matsumura, and M. Nakamura (2000)
J. Biol. Chem. 275, 11154-11163
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Identification of Poly(ADP-Ribose) Polymerase as a Transcriptional Coactivator of the Human T-Cell Leukemia Virus Type 1 Tax Protein.
M. G. Anderson, K. E. S. Scoggin, C. M. Simbulan-Rosenthal, and J. A. Steadman (2000)
J. Virol. 74, 2169-2177
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Induction of Bcl-xL Expression by Human T-Cell Leukemia Virus Type 1 Tax through NF-kappa B in Apoptosis-Resistant T-Cell Transfectants with Tax.
T. Tsukahara, M. Kannagi, T. Ohashi, H. Kato, M. Arai, G. Nunez, Y. Iwanaga, N. Yamamoto, K. Ohtani, M. Nakamura, et al. (1999)
J. Virol. 73, 7981-7987
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Hypopigmented Mycosis Fungoides Associated With Human T Cell Lymphotropic Virus Type I Tax in a Pediatric Patient.
D. Zucker-Franklin, M. K. Kosann, B. A. Pancake, D. L. Ramsay, and N. A. Soter (1999)
Pediatrics 103, 1039-1044
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Human T-cell leukemia retrovirus-Tax protein is a repressor of nuclear receptor signaling.
V. Doucas and R. M. Evans (1999)
PNAS 96, 2633-2638
   Abstract »    Full Text »    PDF »
Phosphorylation of the Human T-Cell Leukemia Virus Type 1 Transactivator Tax on Adjacent Serine Residues Is Critical for Tax Activation.
F. Bex, K. Murphy, R. Wattiez, A. Burny, and R. B. Gaynor (1999)
J. Virol. 73, 738-745
   Abstract »    Full Text »    PDF »
Walleye Retroviruses Associated with Skin Tumors and Hyperplasias Encode Cyclin D Homologs.
L. A. LaPierre, J. W. Casey, and D. L. Holzschu (1998)
J. Virol. 72, 8765-8771
   Abstract »    Full Text »    PDF »
Involvement of NF-AT in Type I Human T-cell Leukemia Virus Tax-mediated Fas Ligand Promoter Transactivation.
I. Rivera, E. W. Harhaj, and S.-C. Sun (1998)
J. Biol. Chem. 273, 22382-22388
   Abstract »    Full Text »    PDF »
Activation of Human T-Cell Leukemia Virus Type 1 tax Gene Expression in Chronically Infected T Cells.
H.-C. Lin, C. S. Dezzutti, R. B. Lal, and A. B. Rabson (1998)
J. Virol. 72, 6264-6270
   Abstract »    Full Text »    PDF »
Human T-Cell Leukemia Virus Type 1 Tax and Cell Cycle Progression: Role of Cyclin D-cdk and p110Rb.
C. Neuveut, K. G. Low, F. Maldarelli, I. Schmitt, F. Majone, R. Grassmann, and K.-T. Jeang (1998)
Mol. Cell. Biol. 18, 3620-3632
   Abstract »    Full Text »
Differential Transcriptional Activation by Human T-Cell Leukemia Virus Type 1 Tax Mutants Is Mediated by Distinct Interactions with CREB Binding Protein and p300.
F. Bex, M.-J. Yin, A. Burny, and R. B. Gaynor (1998)
Mol. Cell. Biol. 18, 2392-2405
   Abstract »    Full Text »
Specific interaction of HTLV tax protein and a human type IV neuronal intermediate filament protein.
T. R. Reddy, X. Li, Y. Jones, M. H. Ellisman, G. Y. Ching, R. K. H. Liem, and F. Wong-Staal (1998)
PNAS 95, 702-707
   Abstract »    Full Text »    PDF »
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.
I. Schmitt, O. Rosin, P. Rohwer, M. Gossen, and R. Grassmann (1998)
J. Virol. 72, 633-640
   Abstract »    Full Text »    PDF »
Interaction between Cell Cycle Regulator, E2F-1, and NF-kappa B Mediates Repression of HIV-1 Gene Transcription.
M. Kundu, M. Guermah, R. G. Roeder, S. Amini, and K. Khalili (1997)
J. Biol. Chem. 272, 29468-29474
   Abstract »    Full Text »    PDF »
Efficient Transfer of Synthetic Ribozymes into Cells Using Hemagglutinating Virus of Japan (HVJ)-Cationic Liposomes. APPLICATION FOR RIBOZYMES THAT TARGET HUMAN T-CELL LEUKEMIA VIRUS TYPE I tax/rex mRNA.
I. Kitajima, N. Hanyu, Y. Soejima, R. Hirano, S. Arahira, S. Yamaoka, R. Yamada, I. Maruyama, and Y. Kaneda (1997)
J. Biol. Chem. 272, 27099-27106
   Abstract »    Full Text »    PDF »
Identification of an Osteoclast Transcription Factor That Binds to the Human T Cell Leukemia Virus Type I-Long Terminal Repeat Enhancer Element.
D. Inoue, P. Santiago, W. C. Horne, and R. Baron (1997)
J. Biol. Chem. 272, 25386-25393
   Abstract »    Full Text »    PDF »
Cytokine Expression and Tumorigenicity of Large Granular Lymphocytic Leukemia Cells From Mice Transgenic for the tax Gene of Human T-Cell Leukemia Virus Type I.
W. J. Grossman and L. Ratner (1997)
Blood 90, 783-794
   Abstract »    Full Text »    PDF »
Binding and Functional Effects of Transcriptional Factor Sp1 on the Murine Interleukin-6 Promotor.
S.-H. Kang, D. A. Brown, I. Kitajima, X. Xu, O. Heidenreich, S. Gryaznov, and M. Nerenberg (1996)
J. Biol. Chem. 271, 7330-7335
   Abstract »    Full Text »    PDF »
Enhanced E-cadherin expression and increased calcium-dependent cell-cell adhesion in human T-cell leukemia virus type I Tax-expressing PC12 cells.
I. Kitajima, K. Kawahara, N. Hanyu, H. Shin, T. Tokioka, Y. Soejima, J. Tsutsui, M. Ozawa, T. Shimayama, and I. Maruyama (1996)
J. Cell Sci. 109, 609-617
   Abstract »    PDF »
Transcriptional Repression of p53 by Human T-cell Leukemia Virus Type I Tax Protein.
M. N. Uittenbogaard, H. A. Giebler, D. Reisman, and J. K. Nyborg (1995)
J. Biol. Chem. 270, 28503-28506
   Abstract »    Full Text »    PDF »
Ablation of transplanted HTLV-I Tax-transformed tumors in mice by antisense inhibition of NF-kappa B.
I Kitajima, T Shinohara, J Bilakovics, D. Brown, X Xu, and M Nerenberg (1992)
Science 258, 1792-1795
   Abstract »    PDF »
Transgenic models of tumor development.
J. Adams and S Cory (1991)
Science 254, 1161-1167
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Viruses in human cancers.
H zur Hausen (1991)
Science 254, 1167-1173
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Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I.
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Science 253, 1026-1028
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Progressive encephalopathy and myopathy in transgenic mice expressing human foamy virus genes.
K Bothe, A Aguzzi, H Lassmann, A Rethwilm, and I Horak (1991)
Science 253, 555-557
   Abstract »    PDF »
HTLV-I trans-activator protein, tax, is a trans-repressor of the human beta-polymerase gene.
K. Jeang, S. Widen, O. Semmes 4th, and S. Wilson (1990)
Science 247, 1082-1084
   Abstract »    PDF »
Transgenic mice as probes into complex systems.
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Science 246, 1265-1275
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J. W. Lee, E. P. Fox, P. Rodgers-Johnson, C. J. Gibbs Jr, E. DeFreitas, A. Manns, W. Blattner, J. Cotelingam, P. Piccardo, C. Mora, et al. (1989)
Ann Intern Med 110, 239-241
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Cellular transcription factors and regulation of IL-2 receptor gene expression by HTLV-I tax gene product.
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Science 241, 89-92
   Abstract »    PDF »
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R Jaenisch (1988)
Science 240, 1468-1474
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Science 240, 643-646
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A transgenic mouse model for human neurofibromatosis.
S. Hinrichs, M Nerenberg, R. Reynolds, G Khoury, and G Jay (1987)
Science 237, 1340-1343
   Abstract »    PDF »
Accelerated G1 Phase Progression Induced by the Human T Cell Leukemia Virus Type I (HTLV-I) Tax Oncoprotein.
F. J. Lemoine and S. J. Marriott (2001)
J. Biol. Chem. 276, 31851-31857
   Abstract »    Full Text »    PDF »


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