Human T-Cell Leukemia Virus Type 1 Tax Shuttles between Functionally Discrete Subcellular Targets

Burton, Molly; Upadhyaya, Cherrag D.; Maier, Bernhard; Hope, Thomas J.; Semmes, O. John

doi:10.1128/jvi.74.5.2351-2364.2000

Cited by 70 publications

(76 citation statements)

References 60 publications

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“…In this respect it appears that subcellular localization of the viral protein Tax would be an effective means of regulating virus-cell interactions. We previously reported that Tax can shuttle between the nucleus and cytoplasm (30) and would favor a model ascribing control of overall Tax function via regulation of targeting to subnuclear sites. Uncovering the mechanism by which Tax targets to multiple subcellular sites would help explain the pleiotropic functionality of this protein.…”

Section: Figmentioning

confidence: 99%

Human T-cell Leukemia Virus-I Tax Oncoprotein Functionally Targets a Subnuclear Complex Involved in Cellular DNA Damage-Response

Haoudi

Daniels

Wong

et al. 2003

Journal of Biological Chemistry

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The virally encoded oncoprotein Tax has been implicated in HTLV-1-mediated cellular transformation. The exact mechanism by which this protein contributes to the oncogenic process is not known. However, it has been hypothesized that Tax induces genomic instability via repression of cellular DNA repair. We examined the effect of de novo Tax expression upon the cell cycle, because appropriate activation of cell cycle checkpoints is essential to a robust damage-repair response. Upon induction of tax expression, Jurkat T-cells displayed a pronounced accumulation in G 2 /M that was reversible by caffeine. We examined the G 2 -specific checkpoint signaling response in these cells and found activation of the ATM/chk2-mediated pathway, whereas the ATR/ chk1-mediated response was unaffected. Immunoprecipitation with anti-chk2 antibody results in co-precipitation of Tax demonstrating a direct interaction of Tax with a chk2-containing complex. We also show that Tax targets a discrete nuclear site and co-localizes with chk2 and not chk1. This nuclear site, previously identified as Tax Speckled Structures (TSS), also contains the early damage response factor 53BP1. The recruitment of 53BP1 to TSS is dependent upon ATM signaling and requires expression of Tax. Specifically, Tax expression induces redistribution of diffuse nuclear 53BP1 to the TSS foci. Taken together these data suggest that the TSS describe a unique nuclear site involved in DNA damage recognition, repair response, and cell cycle checkpoint activation. We suggest that association of Tax with this multifunctional subnuclear site results in disruption of a subset of the site-specific activities and contributes to cellular genomic instability.

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Section: Figmentioning

confidence: 99%

Human T-cell Leukemia Virus-I Tax Oncoprotein Functionally Targets a Subnuclear Complex Involved in Cellular DNA Damage-Response

Haoudi

Daniels

Wong

et al. 2003

Journal of Biological Chemistry

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“…Spot 30 in panel A and small arrows in panel B and C are tropomyosin and were used as an internal standard control. D, typical MALDI-TOF mass spectra of in-gel digested sample spots (1,2,4,6,7,16,19, and 25) from 2-D PAGE. Star-labeled peaks of each spectrum (Table I) are peptides matched for specific protein candidates found in the data base.…”

Section: Fig 2 Two-dimensional Electrophoresis Pattern Of the Tax 1mentioning

confidence: 99%

“…CREB-dependent) and cytoplasmic (e.g. NFB-dependent) levels, functioning through shuttling proteins between these two compartments (2,3).…”

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confidence: 99%

Protein Profile of Tax-associated Complexes

Bottazzi

Fuente

et al. 2004

Journal of Biological Chemistry

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Infection with human T-cell leukemia virus type 1 (HTLV-1) results in adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax, a 40-kDa protein, regulates viral and cellular transcription, host signal transduction, the cell cycle, and apoptosis. Tax has been shown to modulate cellular CREB and NFB pathways; however, to date, its role in binding to various host cellular proteins involved in tumorigenesis has not been fully described. In this study, we describe the Tax-associated proteins and their functions in cells using several approaches. Tax eluted from a sizing column mostly at an apparent molecular mass of 1800 kDa. Following Tax immunoprecipitation, washes with high salt buffer, two-dimensional gel separation, and mass spectrometric analysis, a total of 32 proteins was identified. Many of these proteins belong to the signal transduction and cytoskeleton pathways and transcription/chromatin remodeling. A few of these proteins, including TXBP151, have been shown previously to bind to Tax. The interaction of Tax with small GTPase-cytoskeleton proteins, such as ras GAP 1m , Rac1, Cdc42, RhoA, and gelsolin, indicates how Tax may regulate migration, invasion, and adhesion in T-cell cancers. Finally, the physical and functional association of Tax with the chromatin remodeling SWI/SNF complex was assessed using in vitro chromatin remodeling assays, chromatin remodeling factor BRG1 mutant cells, and RNA interference experiments. Collectively, Tax is able to bind and regulate many cellular proteins that regulate transcription and cytoskeletal related pathways, which might explain the pleiotropic effects of Tax leading to T-cell transformation and leukemia in HTLV-1-infected patients.Infection with human T-cell leukemia virus type 1 (HTLV-1) 1 results in adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The Tax protein encoded by HTLV-1 plays a central role in the development of both adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Although Tax itself does not bind to DNA directly or function as an enzyme, its ability to regulate multiple cellular responses is conferred by its protein-protein interactions with various host cellular factors. Importantly, HTLV-1-mediated activation of the host T-cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction, cell cycle control, and apoptosis. Therefore, understanding how Tax controls these pathways is of significant importance. Tax targets several transcriptional pathways including CREB/activating transcription factor, NFB, and multiple other factors including cell cycle regulators, such as cyclins D2 and D3, the mitotic checkpoint regulator MAD1, the cyclin-dependent kinases (Cdk) Cdk4 and Cdk6, Cdk inhibitors (p16/INK4A and p21/Waf1), and the tumor suppressor p53 (1). Moreover, Tax regulation is observed at both nuclear (e.g. CREB-dependent) and cytoplasmic (e.g. NFB-dependent) levels, functioning through shuttl...

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“…Specifically, with respect to the regulation of multiple Tax activities, it has been noted that mutation or deletion of individual domains results in a selective loss of function (13). Important domains for Tax function include a nuclear localization signal (13,14), nuclear export signal (15,16), activation specific region (17), two leucine zip-like domains (18,19), and a zinc-finger domain (20). Mutation of a number of individual serine residues in Tax have been shown to alter its ability to trans-activate either CREB or NF-B-responsive promoters (13).…”

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confidence: 99%

Site-specific Phosphorylation Differentiates Active from Inactive Forms of the Human T-cell Leukemia Virus Type 1 Tax Oncoprotein

et al. 2006

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The human T-cell leukemia virus type 1 oncoprotein Tax is a phosphoprotein with a predominately nuclear subcellular localization that accomplishes multiple functions via protein-protein interactions. It has been proposed that regulation of this protein's pleiotropic functions may be accomplished through phosphorylation of specific amino acid residues. We have conducted a phosphoryl mapping of mammalian-expressed Tax protein using a combination of affinity purification, liquid chromatography tandem mass spectrometry, and site-directed substitution mutational analysis. We achieved physical coverage of 77% of the Tax sequence and identified four novel sites of phosphorylation at Thr-48, Thr-184, Thr-215, and Ser-336. Previously identified potential serine phosphorylation sites at Ser-10, Ser-77, and Ser-274 could not be confirmed by mass spectrometry. The functional significance of these novel phosphorylation events was evaluated by mutational analysis and subsequent evaluation for activity via both CREB and NF-B-responsive promoters. Our results demonstrate that phosphorylation at Thr-215 is associated with loss of both Tax functions, phosphorylation at Thr-48 was specifically deficient for activation via NF-B, and phosphorylation at Thr-184 and Ser-336 had no effect on these Tax functions. Semiquantitation of phosphopeptides revealed that the majority of Tax was phosphorylated at Thr-48, Thr-184, Thr-215, and Ser-336, whereas only a minor population of Tax was phosphorylated at either Ser-300 or Ser-301. These results suggest that both positive and negative phosphorylation signals result in the maintenance of a subfraction of Tax as "active" protein. Human T-cell leukemia virus type 1 (HTLV-1)2 is a human transforming retrovirus. Infection with HTLV-1 can give rise to adult T-cell leukemia and HTLV-1-associated myelopathy/ tropical spastic paraparesis as well as other subneoplastic conditions (1-5). Although cellular transformation can be achieved by expression of a single viral transactivating protein, Tax, the exact mechanism of transformation is not known (6). Tax is thought to induce genomic instability and, thus, to contribute to cellular transformation through interaction with cellular proteins involved in cell cycle control and the DNA damage repair response (7-11). In addition, Tax can activate or repress a variety of cellular genes predominately through the CREB (cAMP-response element-binding protein) and NF-B pathways (6, 12). Thus, uncovering the regulatory mechanism for controlling the various Tax activities is critical to understanding HTLV-1-mediated cellular transformation.There have been several structure-function studies of the Tax protein predominately utilizing molecular biology techniques. Specifically, with respect to the regulation of multiple Tax activities, it has been noted that mutation or deletion of individual domains results in a selective loss of function (13). Important domains for Tax function include a nuclear localization signal (13, 14), nuclear export signal (15, 16), activatio...

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Human T-Cell Leukemia Virus Type 1 Tax Shuttles between Functionally Discrete Subcellular Targets

Cited by 70 publications

References 60 publications

Human T-cell Leukemia Virus-I Tax Oncoprotein Functionally Targets a Subnuclear Complex Involved in Cellular DNA Damage-Response

Human T-cell Leukemia Virus-I Tax Oncoprotein Functionally Targets a Subnuclear Complex Involved in Cellular DNA Damage-Response

Protein Profile of Tax-associated Complexes

Site-specific Phosphorylation Differentiates Active from Inactive Forms of the Human T-cell Leukemia Virus Type 1 Tax Oncoprotein

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