Genomes and Genes
tax gene products
Summary: Transcriptional trans-acting proteins of the promoter elements found in the long terminal repeats (LTR) of HUMAN T-LYMPHOTROPIC VIRUS 1 and HUMAN T-LYMPHOTROPIC VIRUS 2. The tax (trans-activator x; x is undefined) proteins act by binding to enhancer elements in the LTR.
- Ye J, Silverman L, Lairmore M, Green P. HTLV-1 Rex is required for viral spread and persistence in vivo but is dispensable for cellular immortalization in vitro. Blood. 2003;102:3963-9 pubmed..However, Rex is critical for efficient infection of cells and persistence in vivo. ..
- Mori N, Fujii M, Hinz M, Nakayama K, Yamada Y, Ikeda S, et al. 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;99:378-85 pubmed..Our findings link HTLV-I infection to changes in cellular D-type cyclin gene expression, transformation of T cells and subsequent development of T-cell leukemia. ..
- 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;42:6921-8 pubmed..We also report that Tax40N retains the transactivation ability. These results of in vitro studies demonstrate a potentially novel, p16-independent route to regulate CDK4 activity by the Tax oncoprotein in HTLV-1 infected cells. ..
- Mizuguchi M, Asao H, Hara T, Higuchi M, Fujii M, Nakamura M. Transcriptional activation of the interleukin-21 gene and its receptor gene by human T-cell leukemia virus type 1 Tax in human T-cells. J Biol Chem. 2009;284:25501-11 pubmed publisher..The study suggests insights into cytokine-dependent aberrant growth of HTLV-1-infected T-cells and the molecular basis of different pathogenicity between HTLV-1 and HTLV-2...
- Haoudi A, Semmes O. The HTLV-1 tax oncoprotein attenuates DNA damage induced G1 arrest and enhances apoptosis in p53 null cells. Virology. 2003;305:229-39 pubmed..These data demonstrate that Tax-mediated cellular genomic instability arises from attenuation of cell-cycle checkpoint and imply a clonal dependence on p53 status separate from genomic integrity. ..
- Fryrear K, Durkin S, Gupta S, Tiedebohl J, Semmes O. Dimerization and a novel Tax speckled structure localization signal are required for Tax nuclear localization. J Virol. 2009;83:5339-52 pubmed publisher..Thus, we defined additional domains in Tax specific for nuclear localization and subnuclear targeting. Our results reveal a more complex network for regulation of Tax subcellular localization and subsequent function. ..
- Shembade N, Harhaj N, Yamamoto M, Akira S, Harhaj E. The human T-cell leukemia virus type 1 Tax oncoprotein requires the ubiquitin-conjugating enzyme Ubc13 for NF-kappaB activation. J Virol. 2007;81:13735-42 pubmed..Collectively, our results reveal that Ubc13 is essential for Tax ubiquitination, its interaction with NEMO, and Tax-mediated NF-kappaB activation...
- 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;279:31991-4 pubmed
- Gilli S, Salles T, Saad S. Regulation of the GATA3 promoter by human T-cell lymphotropic virus type I Tax protein. J Cell Biochem. 2004;93:1178-87 pubmed..This interaction may be involved in the pathophysiology of adult T-cell leukemia/lymphoma (ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). ..
- Kawakami H, Tomita M, Matsuda T, Ohta T, Tanaka Y, Fujii M, et al. Transcriptional activation of survivin through the NF-kappaB pathway by human T-cell leukemia virus type I tax. Int J Cancer. 2005;115:967-74 pubmed..Our findings suggest that activated NF-kappaB signaling contributes directly to malignant progression of ATL by preventing apoptosis, acting through the prosurvival protein survivin. ..
- 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 pubmed..Since the N- and C-terminus of CDK4 are neighboring in the predicted three-dimensional protein structure, it is conceivable that they comprise a single binding domain, which interacts with the Tax N-terminus. ..
- Chevalier S, Meertens L, Pise Masison C, Calattini S, Park H, Alhaj A, et al. The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax. Oncogene. 2006;25:4470-82 pubmed..This suggests the possible occurrence of lymphoproliferative disorders among HTLV-3-infected populations...
- Jain P, Mostoller K, Flaig K, Ahuja J, Lepoutre V, Alefantis T, et al. 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;282:34581-93 pubmed
- Yamano Y, Nagai M, Brennan M, Mora C, Soldan S, Tomaru U, et al. Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mRNA with proviral DNA load, virus-specific CD8(+) T cells, and disease severity in HTLV-1-associated myelopathy (HAM/TSP). Blood. 2002;99:88-94 pubmed..These data suggest that increased HTLV-1 expression plays an important role in the pathogenesis of HAM/TSP, and the HTLV-1 tax mRNA level could be a useful predictor of disease progression in patients with HAM/TSP...
- Kehn K, Deng L, de La Fuente C, Strouss K, Wu K, Maddukuri A, et al. The role of cyclin D2 and p21/waf1 in human T-cell leukemia virus type 1 infected cells. Retrovirology. 2004;1:6 pubmed..These two distinct functional and physical activities of p21/waf1 suggest that RNA tumor viruses manipulate the G1/S checkpoint by deregulating cyclin and cdk complexes. ..
- Dodon M, 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;85:1921-32 pubmed..As IL17 upregulates the expression of several pro-inflammatory cytokines, these observations provide new insights into the involvement of the Tax protein in the pathophysiology of HTLV-1-associated inflammatory disorders. ..
- Harashima N, Kurihara K, Utsunomiya A, Tanosaki R, Hanabuchi S, Masuda M, et al. Graft-versus-Tax response in adult T-cell leukemia patients after hematopoietic stem cell transplantation. Cancer Res. 2004;64:391-9 pubmed..These observations suggested that reconstituted immunity against antigen presentation in ATL patients after HSCT resulted in strong and selective graft-versus-HTLV-I response, which might contribute to graft-versus-leukemia effects. ..
- Basbous J, Bazarbachi A, Granier C, Devaux C, Mesnard J. The central region of human T-cell leukemia virus type 1 Tax protein contains distinct domains involved in subunit dimerization. J Virol. 2003;77:13028-35 pubmed..Moreover, the Tax mutants M22 (T130A and L131S) and M29 (K189A and R190S), with amino acid substitutions located in DD1 and DD2, respectively, were found to be impaired in Tax self-association. ..
- Neuveut C, Jeang K. Cell cycle dysregulation by HTLV-I: role of the tax oncoprotein. Front Biosci. 2002;7:d157-63 pubmed..Here, we review extant data on how Tax targets cyclins, inhibitors of cyclin dependent kinase, as well as cellular sentries for DNA-damage. ..
- Ku S, Lee J, Lau J, Gurumurthy M, Ng R, Lwa S, et al. 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;82:4343-53 pubmed publisher..Collectively, our study demonstrates a novel host-virus interaction between a cellular factor XBP-1 and transcriptional regulation of HTLV-1...
- Peloponese J, Jeang K. 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;281:8927-38 pubmed..Tax is shown to activate activator protein-1 through the phosphatidylinositol 3-kinase/Akt pathway. ..
- Zhao T, Yasunaga J, Satou Y, Nakao M, Takahashi M, Fujii M, et al. Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kappaB. Blood. 2009;113:2755-64 pubmed publisher..Selective suppression of the classical NF-kappaB pathway by HBZ renders the alternative NF-kappaB pathway predominant after activation of NF-kappaB by Tax or other stimuli, which might be critical for oncogenesis...
- Torgeman A, Ben Aroya Z, Grunspan A, Zelin E, Butovsky E, Hallak M, et al. Activation of HTLV-I long terminal repeat by stress-inducing agents and protection of HTLV-I-infected T-cells from apoptosis by the viral tax protein. Exp Cell Res. 2001;271:169-79 pubmed
- Liang M, Geisbert T, Yao Y, Hinrichs S, Giam C. Human T-lymphotropic virus type 1 oncoprotein tax promotes S-phase entry but blocks mitosis. J Virol. 2002;76:4022-33 pubmed..PX1 and MT4 may have been selected to harbor somatic mutations that allow a bypass of the Tax-induced block in mitosis. ..
- Shoji T, Higuchi M, Kondo R, Takahashi M, Oie M, Tanaka Y, et al. Identification of a novel motif responsible for the distinctive transforming activity of human T-cell leukemia virus (HTLV) type 1 Tax1 protein from HTLV-2 Tax2. Retrovirology. 2009;6:83 pubmed publisher..This distinction was mediated by at least two Tax1 specific functions, an interaction with host cellular factors through the PDZ domain binding motif (PBM) and the activation of NF-kappa B2 (NF-kappa B2)/p100...
- Livengood J, Scoggin K, Van Orden K, McBryant S, Edayathumangalam R, Laybourn P, et al. p53 Transcriptional activity is mediated through the SRC1-interacting domain of CBP/p300. J Biol Chem. 2002;277:9054-61 pubmed..The identity of the p53.CR2 interaction indicates that at least three distinct sites on CBP/p300 may participate in mediating p53 transactivation. ..
- Rauch D, Gross S, Harding J, Niewiesk S, Lairmore M, Piwnica Worms D, et al. Imaging spontaneous tumorigenesis: inflammation precedes development of peripheral NK tumors. Blood. 2009;113:1493-500 pubmed publisher..The use of BLI expands our ability to interrogate the role of Tax in tumorigenesis in vivo and has made the association of inflammation with tumor initiation amenable for study. ..
- Jin Z, Nagakubo D, Shirakawa A, Nakayama T, Shigeta A, Hieshima K, et al. CXCR7 is inducible by HTLV-1 Tax and promotes growth and survival of HTLV-1-infected T cells. Int J Cancer. 2009;125:2229-35 pubmed publisher..Taken together, CXCR7 is inducible by Tax and may play an important role in HTLV-1-induced immortalization of T cells by promoting growth and survival of HTLV-1-infected T cells. ..
- Hivin P, Gaudray G, Devaux C, Mesnard J. Interaction between C/EBPbeta and Tax down-regulates human T-cell leukemia virus type I transcription. Virology. 2004;318:556-65 pubmed..In conclusion, we propose that during cell activation events, which stimulate the Tax synthesis, C/EBPbeta may down-regulate the level of HTLV-I expression to escape the cytotoxic-T-lymphocyte response. ..
- Chandhasin C, Ducu R, Berkovich E, Kastan M, Marriott S. Human T-cell leukemia virus type 1 tax attenuates the ATM-mediated cellular DNA damage response. J Virol. 2008;82:6952-61 pubmed publisher..Attempts to replicate in the presence of these lesions would result in gradual accumulation of mutations, leading to genome instability and cellular transformation. ..
- Chin K, Chun A, Ching Y, Jeang K, Jin D. Human T-cell leukemia virus oncoprotein tax represses nuclear receptor-dependent transcription by targeting coactivator TAX1BP1. Cancer Res. 2007;67:1072-81 pubmed..We propose that Tax-TAX1BP1 interaction mechanistically explains the previously reported repression of nuclear receptor activity by Tax. ..
- O Mahony A, Montano M, Van Beneden K, Chen L, Greene W. Human T-cell lymphotropic virus type 1 tax induction of biologically Active NF-kappaB requires IkappaB kinase-1-mediated phosphorylation of RelA/p65. J Biol Chem. 2004;279:18137-45 pubmed..IKK2 plays a dominant role in signaling for IkappaBalpha degradation, whereas IKK1 appears to play an important role in enhancing the transcriptional activity of NF-kappaB by promoting RelA/p65 phosphorylation. ..
- Chevalier S, Meertens L, Calattini S, Gessain A, Kiemer L, Mahieux R. Presence of a functional but dispensable nuclear export signal in the HTLV-2 Tax protein. Retrovirology. 2005;2:70 pubmed..Finally, we also show that Tax1 NES function is dependent upon the positioning of the nuclear export signal "vis-à-vis" GFP. HTLV-2 Tax NES is functional but dispensable for the protein localization in vitro. ..
- Van Dooren S, Shanmugam V, Bhullar V, Parekh B, Vandamme A, Heneine W, et al. Identification in gelada baboons (Theropithecus gelada) of a distinct simian T-cell lymphotropic virus type 3 with a broad range of Western blot reactivity. J Gen Virol. 2004;85:507-19 pubmed
- Boxus M, Twizere J, Legros S, Dewulf J, Kettmann R, Willems L. The HTLV-1 Tax interactome. Retrovirology. 2008;5:76 pubmed publisher..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...
- Hieshima K, Nagakubo D, Nakayama T, Shirakawa A, Jin Z, Yoshie O. Tax-inducible production of CC chemokine ligand 22 by human T cell leukemia virus type 1 (HTLV-1)-infected T cells promotes preferential transmission of HTLV-1 to CCR4-expressing CD4+ T cells. J Immunol. 2008;180:931-9 pubmed..Thus, HTLV-1-infected T cells produce CCL22 through Tax and selectively interact with CCR4+CD4+ T cells, resulting in preferential transmission of HTLV-1 to CCR4+CD4+ T cells...
- Gupta S, Guo X, Durkin S, Fryrear K, Ward M, Semmes O. Human T-cell leukemia virus type 1 Tax oncoprotein prevents DNA damage-induced chromatin egress of hyperphosphorylated Chk2. J Biol Chem. 2007;282:29431-40 pubmed..We propose that Tax binding via the Chk2 kinase domain sequesters phosphorylated Chk2 within chromatin, thus hindering chromatin egress and appropriate response to DNA damage. ..
- Tsuji T, Sheehy N, Gautier V, Hayakawa H, Sawa H, Hall W. The nuclear import of the human T lymphotropic virus type I (HTLV-1) tax protein is carrier- and energy-independent. J Biol Chem. 2007;282:13875-83 pubmed..These studies suggest that Tax could alter the nucleocytoplasmic distribution of cellular proteins, and this could contribute to the deregulation of cellular processes observed in HTLV-1 infection. ..
- de La Fuente C, Gupta M, Klase Z, Strouss K, Cahan P, McCaffery T, et al. Involvement of HTLV-I Tax and CREB in aneuploidy: a bioinformatics approach. Retrovirology. 2006;3:43 pubmed..These results indicate that the development of aneuploidy in Tax-expressing cells may occur in response to an alteration in the transcription profile, in addition to direct protein interactions. ..
- 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 U S A. 2005;102:18974-9 pubmed publisher..We report that Tax directly binds Ran and Ran-binding protein-1, locates to centrosomes/spindle poles, and causes supernumerary centrosomes...
- 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;24:1914-23 pubmed publisher..Our observation provides insight into the epigenetic regulation of gene expression and the diverse mechanisms of transcriptional regulation using methylated promoters...
- Silbermann K, Schneider G, Grassmann R. Stimulation of interleukin-13 expression by human T-cell leukemia virus type 1 oncoprotein Tax via a dually active promoter element responsive to NF-kappaB and NFAT. J Gen Virol. 2008;89:2788-98 pubmed publisher..Thus, IL13TaxRE in the IL-13 promoter represents a dually active promoter element responsive to NF-kappaB and NFAT. Together, these results indicate that Tax causes IL-13 upregulation in HTLV-1-infected cells via NF-kappaB...
- Cho W, Zhou M, Jang M, Huang K, Jeong S, Ozato K, et al. Modulation of the Brd4/P-TEFb interaction by the human T-lymphotropic virus type 1 tax protein. J Virol. 2007;81:11179-86 pubmed publisher..Our results suggest the possibility that Tax may compete and functionally substitute for Brd4 in P-TEFb regulation...
- Suzuki S, Singhirunnusorn P, Mori A, Yamaoka S, Kitajima I, Saiki I, et al. 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;282:25177-81 pubmed..These results indicate that Tax-mediated TAK1 activation is important for the activation of ATF2 rather than NF-kappaB. ..
- Lemasson I, Polakowski N, Laybourn P, Nyborg J. Transcription regulatory complexes bind the human T-cell leukemia virus 5' and 3' long terminal repeats to control gene expression. Mol Cell Biol. 2004;24:6117-26 pubmed..These data suggest that HTLV-1 transcriptional regulation at both the 5' and 3' LTRs is mediated, in part, through the mutually exclusive binding of Tax and HDACs at the proviral promoters. ..
- Georges S, Giebler H, Cole P, Luger K, Laybourn P, Nyborg J. Tax recruitment of CBP/p300, via the KIX domain, reveals a potent requirement for acetyltransferase activity that is chromatin dependent and histone tail independent. Mol Cell Biol. 2003;23:3392-404 pubmed..Significantly, these observations reveal the presence of one or more CBP/p300 acetyltransferase targets that function specifically on chromatin templates, are independent of the histone tails, and are critical to Tax transactivation. ..
- Wäldele K, Silbermann K, Schneider G, Ruckes T, Cullen B, Grassmann R. Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes. Blood. 2006;107:4491-9 pubmed..Moreover, this points to HIAP-1 as an important target of the HTLV-1-mediated NF-kappaB activation. ..
- Liu B, Hong S, Tang Z, Yu H, Giam C. 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;102:63-8 pubmed..Unscheduled activation of APC(Cdc20) by Tax provides an explanation for the mitotic abnormalities in HTLV-I-infected cells and is likely to play an important role in the development of adult T cell leukemia. ..
- Boxus M, Willems L. Mechanisms of HTLV-1 persistence and transformation. Br J Cancer. 2009;101:1497-501 pubmed publisher..HTLV-1 has elaborated strategies to persist and replicate in the presence of a strong immune response. In this review, we summarise these mechanisms and their contribution to T-cell transformation and ATL development...