Journal articles: 'Oncoproteina Tax'

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Heym, Stefanie, Caroline Mohr, Hanna Engelbrecht, Bernhard Fleckenstein, and Andrea Thoma-Kress. "Alternative NF-κB Signaling Discriminates Induction of the Tumor Marker Fascin by the Viral Oncoproteins Tax-1 and Tax-2 of Human T-Cell Leukemia Viruses." Cancers 14, no. 3 (January 21, 2022): 537. http://dx.doi.org/10.3390/cancers14030537.

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Transcriptional regulation of the actin-bundling protein and tumor marker Fascin is highly diverse depending on cell and tumor type. Previously, we discovered that the viral oncoprotein Tax-1 of human T-cell leukemia virus type 1 (HTLV-1) considerably enhances Fascin expression in T-cells, depending on classical NF-κB signaling. In this study, we asked if the non-oncogenic Tax-2 of the related HTLV-2 is still able to induce Fascin by using luciferase assays, immunoblot, and qPCR. We found that Tax-2 only slightly induces Fascin expression compared to Tax-1; however, both Tax-1 and Tax-2 comparably activated a 1.6 kb fragment in the human Fascin promoter including Tax-responsive elements. Furthermore, we identified a link between Tax-induced activity of the alternative NF-κB pathway and Fascin induction. While treatment with the second mitochondria-derived activator of caspases (SMAC)-mimetic AZD5582, a compound known to robustly activate alternative NF-κB signaling, did not induce Fascin, combination of AZD5582 with activation of classical NF-κB signaling by Tax-2 significantly induced Fascin expression. In conclusion, our data demonstrate that both classical and alternative NF-κB activity are necessary for strong Fascin induction by the viral Tax oncoproteins, thus, shedding new light on the regulation of Fascin in T-cells and during viral transformation.

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Kress, Andrea K., Martina Kalmer, Aileen G. Rowan, Ralph Grassmann, and Bernhard Fleckenstein. "The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-κB signals." Blood 117, no. 13 (March 31, 2011): 3609–12. http://dx.doi.org/10.1182/blood-2010-09-305805.

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AbstractOncogenic transformation of CD4+ T cells by human T-cell lymphotropic virus type 1 (HTLV-1) is understood as the initial step to adult T-cell leukemia/lymphoma, a process that is mainly initiated by perturbation of cellular signaling by the viral Tax oncoprotein, a potent transcriptional regulator. In search of novel biomarkers with relevance to oncogenesis, we identified the tumor marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly up-regulated in both HTLV-1–transformed and adult T-cell leukemia/lymphoma patient-derived CD4+ T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax was sufficient to induce high levels of Fascin. Nuclear factor-κB signals were important for Tax-mediated transcriptional regulation of Fascin in T cells. This suggests that Fascin up-regulation by Tax contributes to the development of HTLV-1–associated pathogenesis.

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Nasr, Rihab, Estelle Chiari, Marwan El-Sabban, Renaud Mahieux, Youmna Kfoury, Mohammad M. Abdulhay, Olivier Hermine, Hugues de Thé, Claudine Pique, and Ali Bazarbachi. "Tax Ubiquitylation and Sumoylation Control the Two Distinct Steps of NF-κB Activation." Blood 106, no. 11 (November 16, 2005): 4353. http://dx.doi.org/10.1182/blood.v106.11.4353.4353.

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Abstract Activation of the NF-κB pathway by the HTLV-I oncoprotein Tax plays a mandatory role in the proliferation and transformation of infected T cells. We have previously demonstrated that Tax is ubiquitylated, mostly on lysine residues located in its carboxy-terminal half. In this study, we investigated the contribution of Tax ubiquitylation on its ability to transactivate the NF-κB pathway. We show that the integrity of C-terminal lysines, and Tax ubiquitylation, are critical for Tax binding to IKK, IKK activation and nuclear translocation of NF-κB. We also report that Tax is post-translationally modified by SUMO on lysine residues also targeted by ubiquitin and that Tax sumoylation occurs in the nucleus and is required for the terminal steps of NF-κB activation. Conversely, Tax ubiquitylation and sumoylation are not involved in CREB activation. Thus, the differential ubiquitylation or sumoylation of the same lysines in Tax regulates essential events controlling the NF-κB pathway, revealing how distinct cellular modifications enrich the functions of this versatile oncoprotein.

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Twizere, Jean-Claude, Jean-Yves Springael, Mathieu Boxus, Arsène Burny, Franck Dequiedt, Jean-François Dewulf, Julie Duchateau, et al. "Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling." Blood 109, no. 3 (September 21, 2006): 1051–60. http://dx.doi.org/10.1182/blood-2006-06-026781.

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AbstractHuman T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene expression leading to T-cell transformation. Guanine nucleotide–binding proteins (G proteins) and G protein–coupled receptors (GPCRs) constitute the largest family of membrane proteins known and are involved in the regulation of most biological functions. Here, we report an interaction between HTLV-1 Tax oncoprotein and the G-protein β subunit. Interestingly, though the G-protein β subunit inhibits Tax-mediated viral transcription, Tax-1 perturbs G-protein β subcellular localization. Functional evidence for these observations was obtained using conditional Tax-1–expressing transformed T-lymphocytes, where Tax expression correlated with activation of the SDF-1/CXCR4 axis. Our data indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell; this could have tremendous implications for new therapeutic strategies.

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Haller, Kerstin, Yalin Wu, Elisabeth Derow, Iris Schmitt, Kuan-Teh Jeang, and Ralph Grassmann. "Physical Interaction of Human T-Cell Leukemia Virus Type 1 Tax with Cyclin-Dependent Kinase 4 Stimulates the Phosphorylation of Retinoblastoma Protein." Molecular and Cellular Biology 22, no. 10 (May 15, 2002): 3327–38. http://dx.doi.org/10.1128/mcb.22.10.3327-3338.2002.

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ABSTRACT The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV-1) induces leukemia in transgenic mice and permanent T-cell growth in vitro. In transformed lymphocytes, it acts as an essential growth factor. Tax stimulates the cell cycle in the G1 phase by activating the cyclin-dependent kinase (CDK) CDK4 and CDK6 holoenzyme complexes. Here we show that Tax directly interacts with CDK4. This binding to CDK4 was specific, since Tax did not bind to either CDK2 or CDK1. The interaction with CDK4/cyclin D complexes was observed in vitro, in transfected fibroblasts, in HTLV-1-infected T cells, and in adult T-cell leukemia-derived cultures. Binding studies with several point and deletion mutants indicated that the N terminus of Tax mediates the interaction with CDK4. The Tax/CDK complex represented an active holoenzyme which capably phosphorylates the Rb protein in vitro and is resistant to repression by the inhibitor p21CIP. Binding-deficient Tax mutants failed to activate CDK4, indicating that direct association with Tax is required for enhanced kinase activity. Tax also increased the association of CDK4 with its positive cyclin regulatory subunit. Thus, protein-protein contact between Tax and the components of the cyclin D/CDK complexes provides a further mechanistic explanation for the mitogenic and immortalizing effects of this HTLV-1 oncoprotein.

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Fryrear, Kimberly A., Xin Guo, Oliver Kerscher, and O. John Semmes. "The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax." Blood 119, no. 5 (February 2, 2012): 1173–81. http://dx.doi.org/10.1182/blood-2011-06-358564.

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AbstractThe Really Interesting New Gene (RING) Finger Protein 4 (RNF4) represents a class of ubiquitin ligases that target Small Ubiquitin-like Modifier (SUMO)–modified proteins for ubiquitin modification. To date, the regulatory function of RNF4 appears to be ubiquitin-mediated degradation of sumoylated cellular proteins. In the present study, we show that the Human T-cell Leukemia Virus Type 1 (HTLV-1) oncoprotein Tax is a substrate for RNF4 both in vivo and in vitro. We mapped the RNF4-binding site to a region adjacent to the Tax ubiquitin/SUMO modification sites K280/K284. Interestingly, RNF4 modification of Tax protein results in relocalization of the oncoprotein from the nucleus to the cytoplasm. Overexpression of RNF4, but not the RNF4 RING mutant, resulted in cytoplasmic enrichment of Tax. The RNF4-induced nucleus-to-cytoplasm relocalization was associated with increased NF-κB–mediated and decreased cAMP Response Element-Binding (CREB)–mediated Tax activity. Finally, depletion of RNF4 by RNAi prevented the DNA damage–induced nuclear/cytoplasmic translocation of Tax. These results provide important new insight into STUbL-mediated pathways that regulate the subcellular localization and functional dynamics of viral oncogenes.

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Ducu, Razvan I., Tajhal Dayaram, and Susan J. Marriott. "The HTLV-1 Tax oncoprotein represses Ku80 gene expression." Virology 416, no. 1-2 (July 2011): 1–8. http://dx.doi.org/10.1016/j.virol.2011.04.012.

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Wu, Xuefeng, Minying Zhang, and Shao-Cong Sun. "Mutual regulation between deubiquitinase CYLD and retroviral oncoprotein Tax." Cell & Bioscience 1, no. 1 (2011): 27. http://dx.doi.org/10.1186/2045-3701-1-27.

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9

Reilly, Patrick T., Joanna Wysocka, and Winship Herr. "Inactivation of the Retinoblastoma Protein Family Can Bypass the HCF-1 Defect in tsBN67 Cell Proliferation and Cytokinesis." Molecular and Cellular Biology 22, no. 19 (October 1, 2002): 6767–78. http://dx.doi.org/10.1128/mcb.22.19.6767-6778.2002.

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ABSTRACT Owing to a single missense mutation in the cell proliferation factor HCF-1, the temperature-sensitive tsBN67 hamster cell line arrests proliferation at nonpermissive temperatures, primarily in a G0/G1 state, and displays temperature-sensitive cytokinesis defects. The HCF-1 mutation in tsBN67 cells also causes a temperature-sensitive dissociation of HCF-1 from chromatin prior to cell proliferation arrest, suggesting that HCF-1-chromatin association is important for mammalian-cell proliferation. Here, we report that the simian virus 40 (SV40) early region, in particular, large T antigen (Tag), and the adenovirus oncoprotein E1A can rescue the tsBN67 cell proliferation defect at nonpermissive temperatures. The SV40 early region rescues the tsBN67 cell proliferation defect without restoring the HCF-1-chromatin association, indicating that these oncoproteins bypass a requirement for HCF-1 function. The SV40 early region also rescues the tsBN67 cytokinesis defect, suggesting that the roles of HCF-1 in cell proliferation and proper cytokinesis are intimately linked. The ability of SV40 Tag and adenovirus E1A to inactivate members of the pRb protein family—pRb, p107, and p130—is important for the bypass of HCF-1 function. These results suggest that HCF-1 regulates mammalian-cell proliferation and cytokinesis, at least in part, by either directly or indirectly opposing pRb family member function.

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10

Scoggin, Kirsten E. S., Aida Ulloa, and Jennifer K. Nyborg. "The Oncoprotein Tax Binds the SRC-1-Interacting Domain of CBP/p300 To Mediate Transcriptional Activation." Molecular and Cellular Biology 21, no. 16 (August 15, 2001): 5520–30. http://dx.doi.org/10.1128/mcb.21.16.5520-5530.2001.

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ABSTRACT Oncogenesis associated with human T-cell leukemia virus (HTLV) infection is directly linked to the virally encoded transcription factor Tax. To activate HTLV-1 transcription Tax interacts with the cellular protein CREB and the pleiotropic coactivators CBP and p300. While extensively studied, the molecular mechanisms of Tax transcription function and coactivator utilization are not fully understood. Previous studies have focused on Tax binding to the KIX domain of CBP, as this was believed to be the key step in recruiting the coactivator to the HTLV-1 promoter. In this study, we identify a carboxy-terminal region of CBP (and p300) that strongly interacts with Tax and mediates Tax transcription function. Through deletion mutagenesis, we identify amino acids 2003 to 2212 of CBP, which we call carboxy-terminal region 2 (CR2), as the minimal region for Tax interaction. Interestingly, this domain corresponds to the steroid receptor coactivator 1 (SRC-1)-interacting domain of CBP. We show that a double point mutant targeted to one of the putative α-helical motifs in this domain significantly compromises the interaction with Tax. We also characterize the region of Tax responsible for interaction with CR2 and show that the previously identified transactivation domain of Tax (amino acids 312 to 319) participates in CR2 binding. This region of Tax corresponds to a consensus amphipathic helix, and single point mutations targeted to amino acids on the face of this helix abolish interaction with CR2 and dramatically reduce Tax transcription function. Finally, we demonstrate that Tax and SRC-1 bind to CR2 in a mutually exclusive fashion. Together, these studies identify a novel Tax-interacting site on CBP/p300 and extend our understanding of the molecular mechanism of Tax transactivation.

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11

Liang, Min-Hui, Thomas Geisbert, Yao Yao, Steven H. Hinrichs, and Chou-Zen Giam. "Human T-Lymphotropic Virus Type 1 Oncoprotein Tax Promotes S-Phase Entry but Blocks Mitosis." Journal of Virology 76, no. 8 (April 15, 2002): 4022–33. http://dx.doi.org/10.1128/jvi.76.8.4022-4033.2002.

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ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) Tax exerts pleiotropic effects on multiple cellular regulatory processes to bring about NF-κB activation, aberrant cell cycle progression, and cell transformation. Here we report that Tax stimulates cellular G1/S entry but blocks mitosis. Tax expression in naive cells transduced with a retroviral vector, pBabe-Tax, leads to a significant increase in the number of cells in the S phase, with an accompanying rise in the population of cells with a DNA content of 4N or more. In all cell types tested, including BHK-21, mouse NIH 3T3, and human diploid fibroblast WI-38, Tax causes an uncoupling of DNA synthesis from cell division, resulting in the formation of multinucleated giant cells and cells with decondensed, highly convoluted and lobulated nuclei that are reminiscent of the large lymphocytes with cleaved or cerebriform nuclei seen in HTLV-1-positive individuals. This contrasts with the Tax-transformed cell lines, PX1 (fibroblast) and MT4 (lymphocyte), which produce Tax at high levels, but without the accompanying late-stage cell cycle abnormalities. PX1 and MT4 may have been selected to harbor somatic mutations that allow a bypass of the Tax-induced block in mitosis.

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Peloponese, Jean-Marie, Junichiro Yasunaga, Takao Kinjo, Koichi Watashi, and Kuan-Teh Jeang. "Peptidylproline cis-trans-Isomerase Pin1 Interacts with Human T-Cell Leukemia Virus Type 1 Tax and Modulates Its Activation of NF-κB." Journal of Virology 83, no. 7 (January 21, 2009): 3238–48. http://dx.doi.org/10.1128/jvi.01824-08.

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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus etiologically causal of adult T-cell leukemia (ATL). The virus encodes a Tax oncoprotein that functions in transcriptional regulation, cell cycle control, and transformation. ATL is a highly virulent cancer that is resistant to chemotherapeutic treatments. To understand this disease better, it is important to comprehend how HTLV-1 promotes cellular growth and survival. Tax activation of NF-κB is important for the proliferation and transformation of virus-infected cells. We show here that prolyl isomerase Pin1 is over expressed in HTLV-1 cell lines; Pin1 binds Tax and regulates Tax-induced NF-κB activation.

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13

Robek, Michael D., and Lee Ratner. "Immortalization of T Lymphocytes by Human T-Cell Leukemia Virus Type 1 Is Independent of the Tax-CBP/p300 Interaction." Journal of Virology 74, no. 24 (December 15, 2000): 11988–92. http://dx.doi.org/10.1128/jvi.74.24.11988-11992.2000.

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ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein is a 40-kDa nuclear phosphoprotein which functions in the viral replication cycle as a transcriptional trans-activator of the viral long terminal repeat. Tax interacts with a variety of different transcription factors, including the CREB binding protein (CBP)/p300 family of transcriptional accessory proteins. We demonstrate that a Tax mutant defective for the CBP/p300 interaction retains the capacity to immortalize primary human T lymphocytes when it is expressed from a functional molecular clone of HTLV-1. Thus, immortalization of HTLV-1-infected cells appears to be independent of Tax-induced alterations in CBP/p300 function.

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Vandermeulen, Charlotte, Tina O’Grady, Jerome Wayet, Bartimee Galvan, Sibusiso Maseko, Majid Cherkaoui, Alice Desbuleux, et al. "The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape." PLOS Pathogens 17, no. 9 (September 20, 2021): e1009919. http://dx.doi.org/10.1371/journal.ppat.1009919.

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Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome.

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Boxus, Mathieu, Jean-Claude Twizere, Sébastien Legros, Richard Kettmann, and Luc Willems. "Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program." Blood 119, no. 1 (January 5, 2012): 151–60. http://dx.doi.org/10.1182/blood-2011-05-356790.

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AbstractThe Tax oncoprotein encoded by the human T-cell leukemia virus type 1 plays a pivotal role in viral persistence and pathogenesis. Human T-cell leukemia virus type 1–infected cells proliferate faster than normal lymphocytes, expand through mitotic division, and accumulate genomic lesions. Here, we show that Tax associates with the minichromosome maintenance MCM2-7 helicase complex and localizes to origins of replication. Tax modulates the spatiotemporal program of origin activation and fires supplementary origins at the onset of S phase. Thereby, Tax increases the DNA replication rate, accelerates S phase progression, but also generates a replicative stress characterized by the presence of genomic lesions. Mechanistically, Tax favors p300 recruitment and histone hyperacetylation at late replication domains, advancing their replication timing in early S phase.

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Sheleg, Sergey V., Jean-Marie Peloponese, Ya-Hui Chi, Yan Li, Michael Eckhaus, and Kuan-Teh Jeang. "Evidence for Cooperative Transforming Activity of the Human Pituitary Tumor Transforming Gene and Human T-Cell Leukemia Virus Type 1 Tax." Journal of Virology 81, no. 15 (May 16, 2007): 7894–901. http://dx.doi.org/10.1128/jvi.00555-07.

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ABSTRACT Aneuploidy is frequent in cancers. Recently it was found that pituitary tumor transforming gene (PTTG; also called Pds1p or securin) is overexpressed in many different tumors. Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that primarily infects CD4+ T lymphocytes and causes adult T-cell leukemia. Here, we report that overexpression of human PTTG cooperated with the HTLV-I Tax oncoprotein in cellular transformation. Coexpression of Tax and PTTG enhanced chromosomal instability and neoplastic changes to levels greater than overexpression of either factor singularly. Cells that overexpressed both PTTG and Tax induced tumors more robustly in nude mice than cells that expressed either PTTG alone or Tax alone.

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Kfoury, Youmna, Rihab Nasr, Arnaud Favre-Bonvin, Marwan El-Sabban, Noemie Renault, Marie-Louise Giron, Hiba El Hajj, et al. "Molecular Mechanisms of NF-kappaB Activation by the HTLV-I Oncoprotein Tax: Role of Post Translational Protein Modification." Blood 110, no. 11 (November 16, 2007): 4159. http://dx.doi.org/10.1182/blood.v110.11.4159.4159.

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Abstract Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T-cells caused by human T cell lymphotropic virus type I (HTLV-I). The Tax viral oncoprotein plays a crucial role in the proliferation and transformation of HTLV-I infected T lymphocytes through various mechanisms, chiefly through activation of the NF-kappaB pathway. We found that ubiquitin binding to Tax C-terminal lysines in the cytoplasm is critical for Tax binding to the IkappaB kinase (IKK) complex and subsequent nuclear translocation of NF-kappaB. Conversely, we demonstrate that the same Tax lysines are modified by SUMO binding in the nucleus, an event required for the formation of Tax nuclear bodies and full NF-kappaB transcriptional activation. We further show that ubiquitylated Tax is not associated with active cytosolic IKK subunits, but binds endogenous IKK subunits and targets them to the centrosome. Indeed, differential ubiquitylation of Tax results in different outcomes: K63-ubiquitylated Tax colocalizes at the centrosome with IKK, while K48-ubiquitylated Tax is degraded by the proteasome. Altogether, these results support a model in which K63-ubiquitylated Tax activates IKK in a centrosome-associated signalosome, leading to the production of Tax-free active cytoplasmic IKK. Thus, ubiquitylation and sumoylation of the same lysine residues of Tax regulate two essential steps controlling NF-kappaB activation, demonstrating how these posttranslational modifications can cooperate to promote Tax-induced transformation. These observations highlight an unsuspected cellular and biochemical complexity in Tax-induced NF-kappaB activation and represents ideal targets for the development of new drugs for ATL therapy.

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Shembade, Noula, Nicole S. Harhaj, Masahiro Yamamoto, Shizuo Akira, and Edward W. Harhaj. "The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-κB Activation." Journal of Virology 81, no. 24 (October 17, 2007): 13735–42. http://dx.doi.org/10.1128/jvi.01790-07.

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ABSTRACT Ubiquitination of the human T-cell leukemia virus 1 Tax oncoprotein provides an important regulatory mechanism that promotes the Tax-mediated activation of NF-κB. However, the type of polyubiquitin chain linkages and the host factors that are required for Tax ubiquitination have not been identified. Here, we demonstrate that Tax polyubiquitin chains are composed predominantly of lysine 63-linked chains. Furthermore, the ubiquitination of Tax is critically dependent on the E2 ubiquitin-conjugating enzyme Ubc13. Tax interacts with Ubc13, and small interfering RNA-mediated knockdown of Ubc13 expression abrogates Tax ubiquitination and the activation of NF-κB. Mouse fibroblasts lacking Ubc13 exhibit impaired Tax activation of NF-κB despite normal tumor necrosis factor- and interleukin-1-mediated NF-κB activation. Finally, the interaction of Tax with NEMO is disrupted in the absence of Tax ubiquitination and Ubc13 expression, suggesting that Tax ubiquitination is critical for NEMO binding. Collectively, our results reveal that Ubc13 is essential for Tax ubiquitination, its interaction with NEMO, and Tax-mediated NF-κB activation.

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Anjos, Gessica Hellen Silva dos, and Klaudia Emanuela Ramos Tenório. "HTLV-1: fatores genéticos e epigenéticos associados ao desenvolvimento de leucemia/linfoma de células t do adulto." Research, Society and Development 11, no. 7 (May 23, 2022): e26211729781. http://dx.doi.org/10.33448/rsd-v11i7.29781.

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Objetivo: Identificar possíveis fatores genéticos e epigenéticos associados ao desenvolvimento da leucemia/linfoma de células T do adulto. Metodologia: Trata-se de trabalho baseado na revisão integrativa da literatura. A busca por artigos foi realizada mediante o uso dos descritores indexados no DeCS (Descritores em Ciências de saúde) e MeSH (Medical Subject Headings), foram incluídos artigos publicados nos últimos 5 anos. Resultados e Discussão: O processo de carcinogênese que culmina na progressão a ATLL possui várias fases em um longo período de tempo. O início do processo neoplásico está relacionado à expressão da oncoproteína viral Tax, que induz a replicação e início do processo de expansão clonal. A oncoproteína HBZ e o RNA HBZ são continuamente transcritos nas células neoplásicas e influenciam no processo de proliferação celular e persistência viral. Além de fatores genéticos que geralmente são mediadas pelas proteínas Tax e HBZ também é necessário alterações epigenéticas, como a acetilação de histonas e metilação do DNA. Conclusão: conclui-se então que fatores genéticos como o Tax, HBZ, FYN, PLCG1, CD247, DLG1, VAV1, ERC1, PRKCQ, CARD11, RELA, IKBKB, TET1, TET2, MLL2, MLL3 DNMT1 e IRF4. E vias epigenéticas que atuam na metilação do DNA e na acetilação de histonas estão envolvidos no processo de carcinogênese mediado pelo HTLV-1.

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Miyazato, Akiko, Sergey Sheleg, Hidekatsu Iha, Yan Li, and Kuan-Teh Jeang. "Evidence for NF-κB- 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." Journal of Virology 79, no. 14 (July 2005): 9346–50. http://dx.doi.org/10.1128/jvi.79.14.9346-9350.2005.

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ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein can repress the transcriptional activity of the tumor suppressor protein p53. However, it remains controversial whether Tax requires NF-κB factors/activity and/or p300/CBP in order to inactivate p53 function. To address this issue, we have investigated Tax's effect on p53's transcriptional activation in IκB-kinase-deficient mouse embryonic fibroblasts (MEFs); some of which are entirely silent for Tax-induced NF-κB activity. We found that, in IKKα−/−, IKKβ−/−, and IKKγ−/− MEFs, p53 activation of a prototypic responsive plasmid (pG13-luciferase) was repressed by wild-type Tax. Curiously, p53's activity in MEFs was also repressed by a p300/CBP-binding deficient Tax protein. Our results highlight the complex nature of Tax-mediated repression of p53- activity, which requires further investigation.

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Nasr, Rihab, Estelle Chiari, Marwan El-Sabban, Renaud Mahieux, Youmna Kfoury, Maher Abdulhay, Victor Yazbeck, et al. "Tax ubiquitylation and sumoylation control critical cytoplasmic and nuclear steps of NF-κB activation." Blood 107, no. 10 (May 15, 2006): 4021–29. http://dx.doi.org/10.1182/blood-2005-09-3572.

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The Tax oncoprotein plays a crucial role in the proliferation and transformation of human T-cell leukemia virus type I (HTLV-I)–infected T lymphocytes through various mechanisms, including activation of the nuclear factor (NF)–κB pathway. We found that cytoplasmic ubiquitylation of Tax C-terminal lysines is critical for Tax binding to the IkappaB kinase complex and subsequent nuclear translocation of RelA. Conversely, we demonstrate that the same lysines are sumoylated in the nucleus, an event required for the formation of RelA/p300-enriched Tax nuclear bodies and full NF-κB transcriptional activation. In contrast, Tax ubiquitylation and sumoylation are dispensable for its activation of cyclic adenosine monophosphate response element binding protein (CREB)–dependent genes. Thus, ubiquitylation and sumoylation of the same residues of Tax regulate 2 essential steps controlling NF-κB activation, demonstrating how these posttranslational modifications can cooperate to promote Tax-induced transformation.

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Neuveut, Christine. "Cell cycle dysregulation by HTLV-I: role of the TAX oncoprotein." Frontiers in Bioscience 7, no. 1-3 (2002): d157. http://dx.doi.org/10.2741/neuveut.

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Wycuff, Diane, R. "The HTLV-I Tax oncoprotein: hyper-tasking at the molecular level." Frontiers in Bioscience 10, no. 1-3 (2005): 620. http://dx.doi.org/10.2741/1558.

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Jeang, Kuan-Teh. "Cell cycle dysregulation by HTLV-I role of the TAX oncoprotein." Frontiers in Bioscience 7, no. 4 (2002): d157–163. http://dx.doi.org/10.2741/a773.

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Cheng, Hua, Tong Ren, and Shao-cong Sun. "New insight into the oncogenic mechanism of the retroviral oncoprotein Tax." Protein & Cell 3, no. 8 (July 21, 2012): 581–89. http://dx.doi.org/10.1007/s13238-012-2047-0.

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Shirinian, Margret, Zakaria Kambris, Lama Hamadeh, Caroline Grabbe, Chloé Journo, Renaud Mahieux, and Ali Bazarbachi. "A Transgenic Drosophila melanogaster Model To Study Human T-Lymphotropic Virus Oncoprotein Tax-1-Driven TransformationIn Vivo." Journal of Virology 89, no. 15 (May 20, 2015): 8092–95. http://dx.doi.org/10.1128/jvi.00918-15.

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Human T-cell lymphotropic virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. HTLV-2 is genetically related to HTLV-1 but does not cause any malignant disease. HTLV-1 Tax transactivator (Tax-1) contributes to leukemogenesis via NF-κB. We describe transgenicDrosophilamodels expressing Tax in the compound eye and plasmatocytes. We demonstrate that Tax-1 but not Tax-2 induces ommatidial perturbation and increased plasmatocyte proliferation and that the eye phenotype is dependent on Kenny (IKKγ/NEMO), thus validating this newin vivomodel.

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Yan, Pengrong, Jing Fu, Zhaoxia Qu, Shirong Li, Takashi Tanaka, Michael J. Grusby, and Gutian Xiao. "PDLIM2 suppresses human T-cell leukemia virus type I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation." Blood 113, no. 18 (April 30, 2009): 4370–80. http://dx.doi.org/10.1182/blood-2008-10-185660.

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AbstractThe mechanisms by which the human T-cell leukemia virus type I (HTLV-I) Tax oncoprotein deregulates cellular signaling for oncogenesis have been extensively studied, but how Tax itself is regulated remains largely unknown. Here we report that Tax was negatively regulated by PDLIM2, which promoted Tax K48-linked polyubiquitination. In addition, PDLIM2 recruited Tax from its functional sites into the nuclear matrix where the polyubiquitinated Tax was degraded by the proteasome. Consistently, PDLIM2 suppressed Tax-mediated signaling activation, cell transformation, and oncogenesis both in vitro and in animal. Notably, PDLIM2 expression was down-regulated in HTLV-I–transformed T cells, and PDLIM2 reconstitution reversed the tumorigenicity of the malignant cells. These studies indicate that the counterbalance between HTLV-I/Tax and PDLIM2 may determine the outcome of HTLV-I infection. These studies also suggest a potential therapeutic strategy for cancers and other diseases associated with HTLV-I infection and/or PDLIM2 deregulation.

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Gatza, Michael L., and Susan J. Marriott. "Genotoxic Stress and Cellular Stress Alter the Subcellular Distribution of Human T-Cell Leukemia Virus Type 1 Tax through a CRM1-Dependent Mechanism." Journal of Virology 80, no. 13 (July 1, 2006): 6657–68. http://dx.doi.org/10.1128/jvi.02270-05.

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ABSTRACT Human T-cell leukemia virus type 1 Tax is a predominantly nuclear viral oncoprotein that colocalizes with cellular proteins in nuclear foci known as Tax speckled structures (TSS). Tax is also diffusely distributed throughout the cytoplasm, where it interacts with and affects the functions of cytoplasmic cellular proteins. Mechanisms that regulate the distribution of Tax between the cytoplasm and nucleus remain to be identified. Since Tax has been shown to promote genome instability by perturbing cell cycle progression and DNA repair mechanisms following DNA damage, we examined the effect of genotoxic stress on the subcellular distribution and interacting partners of Tax. Tax localization was altered in response to various forms of cellular stress, resulting in an increase in cytoplasmic Tax and a decrease in Tax speckled structures. Concomitantly, colocalization of Tax with sc35 (a TSS protein) decreased following stress. Tax translocation required the CRM1 nuclear export pathway, and a transient interaction between Tax and CRM1 was observed following stress. These results suggest that the subcellular distribution of Tax and the interactions between Tax and cellular proteins respond dynamically to cellular stress. Changes in Tax distribution and interacting partners are likely to affect cellular processes that regulate cellular transformation.

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Van, Phillip L., Kyong-Wook Yim, Dong-Yan Jin, George Dapolito, Akihiro Kurimasa, and Kuan-Teh Jeang. "Genetic Evidence of a Role for ATM in Functional Interaction between Human T-Cell Leukemia Virus Type 1 Tax and p53." Journal of Virology 75, no. 1 (January 1, 2001): 396–407. http://dx.doi.org/10.1128/jvi.75.1.396-407.2001.

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ABSTRACT Recent evidence from several investigators suggest that the human T-cell leukemia virus type 1 Tax oncoprotein represses the transcriptional activity of the tumor suppressor protein, p53. An examination of published findings reveals serious controversy as to the mechanism(s) utilized by Tax to inhibit p53 activity and whether the same mechanism is used by Tax in adherent and suspension cells. Here, we have investigated Tax-p53 interaction simultaneously in adherent epithelial (HeLa and Saos) and suspension T-lymphocyte (Jurkat) cells. Our results indicate that Tax activity through the CREB/CREB-binding protein (CBP), but not NF-κB, pathway is needed to repress the transcriptional activity of p53 in all tested cell lines. However, we did find that while CBP binding by Tax is necessary, it is not sufficient for inhibiting p53 function. Based on knockout cell studies, we correlated a strong genetic requirement for the ATM, but not protein kinase-dependent DNA, protein in conferring a Tax-p53-repressive phenotype.

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Kfoury, Youmna, Niclas Setterblad, Marwan El-Sabban, Alessia Zamborlini, Zeina Dassouki, Hiba El Hajj, Olivier Hermine, et al. "Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome." Blood 117, no. 1 (January 6, 2011): 190–99. http://dx.doi.org/10.1182/blood-2010-05-285742.

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AbstractThe human T-lymphotropic virus type I oncoprotein Tax is critical for T-cell transformation, acting mainly through nuclear factor kappa B essential modulator (NEMO) binding and subsequent nuclear factor-κB activation. Tax localizes to Tax nuclear bodies and to the centrosome and is subjected to ubiquitylation and small ubiquitin-like modifier (SUMO)ylation, which are both necessary for complete transcriptional activation. Using the photoconvertible fluorophore Dendra-2 coupled with live video confocal microscopy, we show for the first time that the same Tax molecule shuttles among Tax nuclear bodies and between these nuclear bodies and the centrosome, depending on its posttranslational modifications. Ubiquitylation targets Tax to nuclear bodies to which NEMO is recruited and subsequently SUMOylated. We also demonstrate that Tax nuclear bodies contain the SUMOylation machinery including SUMO and the SUMO conjugating enzyme Ubc9, strongly suggesting that these nuclear bodies represent sites of active SUMOylation. Finally, both ubiquitylation and SUMOylation of Tax control NEMO targeting to the centrosome. Altogether, we are proposing a model where both ubiquitylation and SUMOylation of Tax control the shuttling of Tax and NEMO between the cytoplasmic and nuclear compartments.

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Chandhasin, Chandtip, Razvan I. Ducu, Elijahu Berkovich, Michael B. Kastan, and Susan J. Marriott. "Human T-Cell Leukemia Virus Type 1 Tax Attenuates the ATM-Mediated Cellular DNA Damage Response." Journal of Virology 82, no. 14 (April 23, 2008): 6952–61. http://dx.doi.org/10.1128/jvi.02331-07.

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ABSTRACT Genomic instability, a hallmark of leukemic cells, is associated with malfunctioning cellular responses to DNA damage caused by defective cell cycle checkpoints and/or DNA repair. Adult T-cell leukemia, which can result from infection with human T-cell leukemia virus type 1 (HTLV-1), is associated with extensive genomic instability that has been attributed to the viral oncoprotein Tax. How Tax influences cellular responses to DNA damage to mediate genomic instability, however, remains unclear. Therefore, we investigated the effect of Tax on cellular pathways involved in recognition and repair of DNA double-strand breaks. Premature attenuation of ATM kinase activity and reduced association of MDC1 with repair foci were observed in Tax-expressing cells. Following ionizing radiation-induced S-phase checkpoint activation, Tax-expressing cells progressed more rapidly than non-Tax-expressing cells toward DNA replication. These results demonstrate that Tax expression may allow premature DNA replication in the presence of genomic lesions. Attempts to replicate in the presence of these lesions would result in gradual accumulation of mutations, leading to genome instability and cellular transformation.

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Lodewick, Julie, Isabelle Lamsoul, and Françoise Bex. "Move or Die: the Fate of the Tax Oncoprotein of HTLV-1." Viruses 3, no. 6 (June 15, 2011): 829–57. http://dx.doi.org/10.3390/v3060829.

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Van den Broeke, Anne, Mustapha Oumouna, Terry Beskorwayne, Maud Szynal, Yvette Cleuter, Shawn Babiuk, Claude Bagnis, Philippe Martiat, Arsene Burny, and Philip Griebel. "Cytotoxic responses to BLV tax oncoprotein do not prevent leukemogenesis in sheep." Leukemia Research 34, no. 12 (December 2010): 1663–69. http://dx.doi.org/10.1016/j.leukres.2010.06.003.

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Kehn, Kylene, Cynthia de la Fuente, Katharine Strouss, Reem Berro, Hua Jiang, John Brady, Renaud Mahieux, Anne Pumfery, Maria Elena Bottazzi, and Fatah Kashanchi. "The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation." Oncogene 24, no. 4 (December 6, 2004): 525–40. http://dx.doi.org/10.1038/sj.onc.1208105.

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Yoshida, Mitsuaki. "HTLV-1 oncoprotein Tax deregulates transcription of cellular genes through multiple mechanisms." Journal of Cancer Research and Clinical Oncology 121, no. 9-10 (September 1995): 521–28. http://dx.doi.org/10.1007/bf01197764.

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Mohanty, Suchitra, Teng Han, Young Bong Choi, Alfonso Lavorgna, Jiawen Zhang, and Edward William Harhaj. "The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation." PLOS Pathogens 16, no. 12 (December 23, 2020): e1008504. http://dx.doi.org/10.1371/journal.ppat.1008504.

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), and the neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein persistently activates the NF-κB pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-κB; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify new Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax. Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by co-immunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-κB activation, whereas knockdown of UBE4B impaired Tax-induced NF-κB activation and the induction of NF-κB target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR/Cas9-mediated knockout of UBE4B attenuated both K48- and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-κB activation.

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Fu, Jing, Zhaoxia Qu, Pengrong Yan, Chie Ishikawa, Rami I. Aqeilan, Arnold B. Rabson, and Gutian Xiao. "The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis." Blood 117, no. 5 (February 3, 2011): 1652–61. http://dx.doi.org/10.1182/blood-2010-08-303073.

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Abstract Both the canonical and noncanonical nuclear factor κB (NF-κB) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis.

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Fryrear, Kimberly A., Sarah S. Durkin, Saurabh K. Gupta, Jessica B. Tiedebohl, and O. John Semmes. "Dimerization and a Novel Tax Speckled Structure Localization Signal Are Required for Tax Nuclear Localization." Journal of Virology 83, no. 11 (March 25, 2009): 5339–52. http://dx.doi.org/10.1128/jvi.00232-09.

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ABSTRACT The human T-cell leukemia virus type 1 oncoprotein Tax has pleiotropic activities, a subset of which likely leads to immortalization of T cells. Tax is expressed and known to function in both the cell nucleus and the cytoplasm. Tax has defined nuclear localization (NLS) and nuclear export signals that enable shuttling between the two compartments. In this study, we identified a novel region in Tax that targets the protein to discrete nuclear foci that we have previously termed Tax speckled structures (TSS). We demonstrated that the identified region is both necessary and sufficient for directing proteins to TSS. This novel TSS localization signal (TSLS), spanning amino acids 50 to 75, is separable from and adjacent to the NLS of Tax. Coexpression of a Tax NLS mutant and a Tax TSLS mutant rescued the nuclear entry and subnuclear TSS targeting of both proteins, demonstrating that these signals are independent domains. Our analysis also revealed that Tax proteins deficient for dimerization fail to localize to the nucleus. Consequently, when we restored dimerization via induction of a heterologous “dimerizer” domain, nuclear localization was rescued. 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.

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Yuen, Chun-Kit, Ching-Ping Chan, Sin-Yee Fung, Pei-Hui Wang, Wan-Man Wong, Hei-Man Vincent Tang, Kit-San Yuen, Chi-Ping Chan, Dong-Yan Jin, and Kin-Hang Kok. "Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation." Journal of Virology 90, no. 8 (January 27, 2016): 3902–12. http://dx.doi.org/10.1128/jvi.00129-16.

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ABSTRACTInfection with human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and tropical spastic paraparesis. Type I interferons (IFNs) are key effectors of the innate antiviral response, and IFN-α combined with the nucleoside reverse transcriptase inhibitor zidovudine is considered the standard first-line therapy for ATL. HTLV-1 oncoprotein Tax is known to suppress innate IFN production and response but the underlying mechanisms remain to be fully established. In this study, we report on the suppression of type I IFN production by HTLV-1 Tax through interaction with and inhibition of TBK1 kinase that phosphorylates IRF3. Induced transcription of IFN-β was severely impaired in HTLV-1-transformed ATL cells and freshly infected T lymphocytes. The ability to suppress IRF3 activation was ascribed to Tax. The expression of Tax alone sufficiently repressed the induction of IFN production by RIG-I plus PACT, cGAMP synthase plus STING, TBK1, IKKε, IRF3, and IRF7, but not by IRF3-5D, a dominant-active phosphomimetic mutant. This suggests that Tax perturbs IFN production at the step of IRF3 phosphorylation. Tax mutants deficient for CREB or NF-κB activation were fully competent in the suppression of IFN production. Coimmunoprecipitation experiments confirmed the association of Tax with TBK1, IKKε, STING, and IRF3.In vitrokinase assay indicated an inhibitory effect of Tax on TBK1-mediated phosphorylation of IRF3. Taken together, our findings suggested a new mechanism by which HTLV-1 oncoprotein Tax circumvents the production of type I IFNs in infected cells. Our findings have implications in therapeutic intervention of ATL.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia (ATL), an aggressive and fatal blood cancer, as well as another chronic disabling disease of the spinal cord. Treatments are unsatisfactory, and options are limited. A combination of antiviral cellular protein alpha interferon and zidovudine, which is an inhibitor of a viral enzyme called reverse transcriptase, has been recommended as the standard first-line therapy for ATL. Exactly how HTLV-1 interacts with the cellular machinery for interferon production and action is not well understood. Our work sheds light on the mechanism of action for the inhibition of interferon production by an HTLV-1 oncogenic protein called Tax. Our findings might help to improve interferon-based anti-HTLV-1 and anti-ATL therapy.

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Kohrt, Stephan, Sarah Strobel, Melanie Mann, Heinrich Sticht, Bernhard Fleckenstein, and Andrea Thoma-Kress. "Characterizing the Interaction between the HTLV-1 Transactivator Tax-1 with Transcription Elongation Factor ELL2 and Its Impact on Viral Transactivation." International Journal of Molecular Sciences 22, no. 24 (December 18, 2021): 13597. http://dx.doi.org/10.3390/ijms222413597.

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The human T-cell leukemia virus type 1 (HTLV-1)-encoded transactivator and oncoprotein Tax-1 is essential for HTLV-1 replication. We recently found that Tax-1 interacts with transcription elongation factor for RNA polymerase II 2, ELL2, which enhances Tax-1-mediated transactivation of the HTLV-1 promotor. Here, we characterize the Tax-1:ELL2 interaction and its impact on viral transactivation by confocal imaging, co-immunoprecipitation, and luciferase assays. We found that Tax-1 and ELL2 not only co-precipitate, but also co-localize in dot-like structures in the nucleus. Tax-1:ELL2 complex formation occurred independently of Tax-1 point mutations, which are crucial for post translational modifications (PTMs) of Tax-1, suggesting that these PTMs are irrelevant for Tax-1:ELL2 interaction. In contrast, Tax-1 deletion mutants lacking either N-terminal (aa 1–37) or C-terminal regions (aa 150–353) of Tax-1 were impaired in interacting with ELL2. Contrary to Tax-1, the related, non-oncogenic Tax-2B from HTLV-2B did not interact with ELL2. Finally, we found that ELL2-R1 (aa 1–353), which carries an RNA polymerase II binding domain, and ELL2-R3 (aa 515–640) are sufficient to interact with Tax-1; however, only ELL2-truncations expressing R1 could enhance Tax-1-mediated transactivation of the HTLV-1 promoter. Together, this study identifies domains in Tax-1 and ELL2 being required for Tax-1:ELL2 complex formation and for viral transactivation.

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Lamsoul, Isabelle, Julie Lodewick, Sylvie Lebrun, Robert Brasseur, Arsène Burny, Richard B. Gaynor, and Françoise Bex. "Exclusive Ubiquitination and Sumoylation on Overlapping Lysine Residues Mediate NF-κB Activation by the Human T-Cell Leukemia VirusTax Oncoprotein." Molecular and Cellular Biology 25, no. 23 (December 1, 2005): 10391–406. http://dx.doi.org/10.1128/mcb.25.23.10391-10406.2005.

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ABSTRACT The transcription factor NF-κB is critical for the induction of cancer, including adult T-cell leukemia, which is linked to infection by human T-cell leukemia virus type 1 and the expression of its regulatory protein Tax. Although activation of the NF-κB pathway by Tax involves its interaction with the regulatory subunit of the IκB kinase (IKK) complex, NEMO/IKKγ, the mechanism by which Tax activates specific cellular genes in the nucleus remains unknown. Here, we demonstrate that the attachment of SUMO-1 to Tax regulates its localization in nuclear bodies and the recruitment of both the RelA subunit of NF-κB and free IKKγ in these nuclear structures. However, this sumoylation step is not sufficient for the activation of the NF-κB pathway by Tax. This activity requires the prior ubiquitination and colocalization of ubiquitinated Tax with IKK complexes in the cytoplasm and the subsequent migration of the RelA subunit of NF-κB to the nucleus. Thus, the ubiquitination and sumoylation of Tax function in concert to result in the migration of RelA to the nucleus and its accumulation with IKKγ in nuclear bodies for activation of gene expression. These modifications may result in targets for the treatment of adult T-cell leukemia.

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Xie, Li, Brenda Yamamoto, Abdelali Haoudi, O. John Semmes, and Patrick L. Green. "PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo." Blood 107, no. 5 (March 1, 2006): 1980–88. http://dx.doi.org/10.1182/blood-2005-03-1333.

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HTLV-1 cellular transformation and disease induction is dependent on expression of the viral Tax oncoprotein. PDZ is a modular protein interaction domain used in organizing signaling complexes in eukaryotic cells through recognition of a specific binding motif in partner proteins. Tax-1, but not Tax-2, contains a PDZ-binding domain motif (PBM) that promotes the interaction with several cellular PDZ proteins. Herein, we investigate the contribution of the Tax-1 PBM in HTLV-induced proliferation and immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. We generated several HTLV-1 and HTLV-2 Tax viral mutants, including HTLV-1ΔPBM, HTLV-2+C22(+PBM), and HTLV-2+ C18(ΔPBM). All Tax mutants maintained the ability to significantly activate the CREB/ATF or NFκB signaling pathways. Microtiter proliferation assays revealed that the Tax-1 PBM significantly increases both HTLV-1– and HTLV-2–induced primary T-cell proliferation. In addition, Tax-1 PBM was responsible for the micronuclei induction activity of Tax-1 relative to that of Tax-2. Viral infection and persistence were severely attenuated in rabbits inoculated with HTLV-1ΔPBM. Our results provide the first direct evidence suggesting that PBM-mediated associations between Tax-1 and cellular proteins play a key role in HTLV-induced cell proliferation and genetic instability in vitro and facilitate viral persistence in vivo.

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Twizere, Jean-Claude, Laurent Lefèbvre, Delphine Collete, Christophe Debacq, Patrice Urbain, Hubertine Heremans, Jean-Claude Jauniaux, Arsène Burny, Luc Willems, and Richard Kettmann. "The Homeobox Protein MSX2 Interacts with Tax Oncoproteins and Represses Their Transactivation Activity." Journal of Biological Chemistry 280, no. 33 (June 21, 2005): 29804–11. http://dx.doi.org/10.1074/jbc.m503674200.

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Edwards, Dustin C., and Susan J. Marriott. "Human T-Cell Leukemia Virus Type 1 Tax Relieves Repression of Proliferating Cell Nuclear Antigen Gene Expression." Journal of Virology 82, no. 23 (September 17, 2008): 11714–22. http://dx.doi.org/10.1128/jvi.00356-08.

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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia. The transforming ability of Tax, the viral oncoprotein, is believed to depend on interactions with cell cycle regulators and on transactivation of genes that control cellular proliferation, including proliferating cell nuclear antigen (PCNA), a cofactor associated with DNA replication and repair. Tax associates with cellular transcription factors to alter their affinity for cognate DNA elements, leading to increased or decreased transcription from that promoter. Although it has been demonstrated that Tax transactivates the PCNA promoter, the mechanism of transcriptional activation is unknown. Here we report a cellular complex that binds specifically to a novel site within the minimal Tax-responsive element of the TATAA-less PCNA promoter. Mutation at this binding site or Tax expression inhibited complex formation and increased promoter activity, suggesting that the complex is a transcriptional repressor. The activation of PCNA gene expression by Tax and consequential decrease in nucleotide excision repair mediated by PCNA overexpression could contribute to the reduced DNA repair capacity and genomic instability observed in HTLV-1-infected cells.

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van Orden, K., and J. K. Nyborg. "Insight Into the Tumor Suppressor Function of CBP Through the Viral Oncoprotein Tax." Gene Expression 9, no. 1 (January 1, 2001): 29–36. http://dx.doi.org/10.3727/000000001783992678.

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Cherian, Mathew A., Hicham H. Baydoun, Jacob Al-Saleem, Nikoloz Shkriabai, Mamuka Kvaratskhelia, Patrick Green, and Lee Ratner. "Akt Pathway Activation by Human T-cell Leukemia Virus Type 1 Tax Oncoprotein." Journal of Biological Chemistry 290, no. 43 (August 31, 2015): 26270–81. http://dx.doi.org/10.1074/jbc.m115.684746.

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Gao, Ling, Hongju Deng, Haibo Zhao, Angela Hirbe, John Harding, Lee Ratner, and Katherine Weilbaecher. "HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition." Blood 106, no. 13 (December 15, 2005): 4294–302. http://dx.doi.org/10.1182/blood-2005-04-1730.

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One in 20 carriers of human T-cell leukemia virus type 1 (HTLV-1) will develop adult T-cell leukemia/lymphoma (ATL), a disease frequently associated with hypercalcemia, bone destruction, and a fatal course refractory to current therapies. Overexpression of the HTLV-1–encoded Tax oncoprotein under the human granzyme B promoter causes large granular lymphocytic leukemia/lymphomas in mice. We found that Tax+ mice spontaneously developed hypercalcemia, high-frequency osteolytic bone metastases, and enhanced osteoclast activity. We evaluated Tax tumors for the production of osteoclast-activating factors. Purification of Tax+ tumor cells and nonmalignant tumor-infiltrating lymphocytes demonstrated that each of these populations expressed transcripts for distinct osteoclast-activating factors. We then evaluated the effect of osteoclast inhibition on tumor formation. Mice doubly transgenic for Tax and the osteoclast inhibitory factor, osteoprotegerin, were protected from osteolytic bone disease and developed fewer soft-tissue tumors. Likewise, osteoclast inhibition with bone-targeted zoledronic acid protected Tax+ mice from bone and soft-tissue tumors and prolonged survival. Tax+ mice represent the first animal model of high-penetrance spontaneous osteolytic bone metastasis and underscore the critical role of nonmalignant host cells recruited by tumor cells in the process of cancer progression and metastasis.

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Youn, Hwang-Geum, Jun Matsumoto, Yuetsu Tanaka, and Kunitada Shimotohno. "SR-Related Protein TAXREB803/SRL300 Is an Important Cellular Factor for the Transactivational Function of Human T-Cell Lymphotropic Virus Type 1 Tax." Journal of Virology 77, no. 18 (September 15, 2003): 10015–27. http://dx.doi.org/10.1128/jvi.77.18.10015-10027.2003.

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ABSTRACT Expression of the human T-cell lymphotropic virus type 1 (HTLV-1) genes is transcriptionally activated by the cognate oncoprotein Tax which enhances the binding of the cyclin AMP-responsive element binding protein (CREB) to the Tax responsive element (TxRE) located in its long terminal repeat (LTR). TxRE is highly homologous to the cyclic AMP-responsive element (CRE) except for the GC-rich sequence flanking the CRE. We cloned the cDNA for a cellular factor, TAXREB803, of which the DNA-binding domain bound to TxRE and the binding was dependent on the 3′ GC-rich sequence in TxRE. TAXREB803 is an SR-related protein composed of 2,752 amino acids including numerous arginine/serine (RS) motifs. TAXREB803 enhanced both the Tax dependent transcription and the CREB binding to TxRE in cooperation with Tax. The interaction of TAXREB803 and Tax was detected by coimmunoprecipitation assays as well as by indirect immunofluorescence assays. Significantly, Tax transactivation for the HTLV-1 LTR decreased dramatically when the expression level of the endogenous TAXREB803 was suppressed by the small interfering RNA. These results suggest that TAXREB803 functions as a transcriptional coactivator for Tax and plays a critical role in the expression of HTLV-1 genes.

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Colgin, Mark A., and Jennifer K. Nyborg. "The Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax Inhibits the Transcriptional Activity of c-Myb through Competition for the CREB Binding Protein." Journal of Virology 72, no. 11 (November 1, 1998): 9396–99. http://dx.doi.org/10.1128/jvi.72.11.9396-9399.1998.

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ABSTRACT Tax, the transforming protein of human T-cell leukemia virus type 1 (HTLV-1), is required for strong activation of HTLV-1 transcription. This activation is mediated through interaction with the KIX domain of the cellular coactivator CREB binding protein (CBP). In this study we examined the possibility that the Tax-KIX interaction may mediate effects on cellular gene transcription in vivo, as a growing number of cellular transcription factors have been shown to utilize CBP as a coactivator. We tested the ability of Tax to deregulate the activity of the cellular transcription factor, c-Myb, since both Tax and c-Myb interact with the KIX domain of CBP. Our results show that in vivo, Tax antagonizes the transcriptional activity of c-Myb and, reciprocally, c-Myb antagonizes the transcriptional activity of Tax. Furthermore, c-Myb competes for KIX binding to Tax in vitro, indicating that these two transcription factors bind CBP in a mutually exclusive manner. This novel mechanism of transcriptional interference by Tax may promote globally deregulated cellular gene expression in the HTLV-1-infected cell, possibly leading to leukemogenesis.

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Terme, Jean-Michel, Melanie Wencker, Arnaud Favre-Bonvin, Françoise Bex, Louis Gazzolo, Madeleine Duc Dodon, and Pierre Jalinot. "Cross Talk between Expression of the Human T-Cell Leukemia Virus Type 1 Tax Transactivator and the Oncogenic bHLH Transcription Factor TAL1." Journal of Virology 82, no. 16 (May 21, 2008): 7913–22. http://dx.doi.org/10.1128/jvi.02414-07.

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Abstract:

ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) Tax transactivator is known to induce or repress various cellular genes, several of them encoding transcription factors. As Tax is known to deregulate various basic bHLH factors, we looked more specifically at its effect on TAL1 (T-cell acute lymphoblastic leukemia 1), also known as SCL (stem cell leukemia). Indeed, TAL1 is deregulated in a high percentage of T-cell acute lymphoblastic leukemia cells, and its oncogenic properties are well-established. Here we show that Tax induces transcription of this proto-oncogene by stimulating the activity of the TAL1 gene promoter 1b, through both the CREB and NF-κB pathways. It was also observed that TAL1 upregulates HTLV-1 promoter activity, in either the presence or the absence of Tax. The viral promoter is inhibited in trans by expression of the E2A protein E47, and TAL1 is able to abrogate this inhibition. These data show the existence of a positive feedback loop between Tax and TAL1 expression and support the notion that this proto-oncogene participates in generation of adult T-cell leukemia/lymphoma by increasing the amount of the Tax oncoprotein but also possibly by its own transforming activities.

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Journal articles on the topic 'Oncoproteina Tax'

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