Human T‐cell leukemia virus type 1 Tax activates cyclin‐dependent kinase inhibitor p21/Waf1/Cip1 expression through a p53‐independent mechanism: Inhibition of cdk2

Chowdhury, Iqbal Hossain; Farhadi, Arash; Wang, Xiaofan; Robb, Merlin L.; Birx, Deborah L.; Kim, Jerome H.

doi:10.1002/ijc.11316

Cited by 25 publications

(27 citation statements)

References 64 publications

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“…Tax activates the p21 Waf1/Cip1 promoter in p53 null cells, and increases p21 Waf1/Cip1 expression in Jurkat T cells. These findings suggest that Tax is at least partially responsible for the p53-independent expression of p21 Waf1/Cip1 in HTLV-I-infected cells (Cereseto et al, 1996;Chowdhury et al, 2003). p21 Waf1/Cip1 expression may enhance cell survival through its role in the antiapoptotic machinery (Kawata et al, 2003).…”

Section: Inhibition Of Cki Functionmentioning

confidence: 90%

Molecular mechanisms of cellular transformation by HTLV-1 Tax

2005

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Section: Inhibition Of Cki Functionmentioning

confidence: 90%

Molecular mechanisms of cellular transformation by HTLV-1 Tax

2005

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“…Recent data have indicated that Skp2 is a substrate of the Cdh1-associated APC (APC Cdh1 ) (10,191 The activation of p21 CIP1/WAF1 transcription by Tax has been reported previously (20,21,24,32). These earlier studies have suggested that the Tax-induced increase in p21 CIP1/WAF1 resulted from transactivation via the CREB/ATF-CBP/p300 pathway (24,32). To further study the significance of the Tax-induced cell-cycle arrest, I investigated whether the Tax mutants could transform Rat1 fibroblasts, as had been previously reported for WT-Tax (38,69,89,121,197).…”

Section: Discussionmentioning

confidence: 75%

“…As most Tax (10,47,191). Recent data have indicated that Skp2 is a substrate of the Cdh1-associated APC (APC Cdh1 ) (10,191 The activation of p21 CIP1/WAF1 transcription by Tax has been reported previously (20,21,24,32). These earlier studies have suggested that the Tax-induced increase in p21 CIP1/WAF1 resulted from transactivation via the CREB/ATF-CBP/p300 pathway (24,32).…”

Section: Discussionmentioning

confidence: 80%

“…Tax transactivates the HTLV-1 LTR promoter through its interaction with CREB/ATF-1 (1, 8,152,199,204,205), CBP/p300 (12,58,59,99,106), and the Tax-responsive 21-bp repeat element, and activates the NF-!B pathway (26,82,178,187,192,194) through the interaction with PP2A/IKK" (44). In addition to its transactivation functions, Tax also impacts on many aspects of the cell cycle: activating G 1 /S transition (90,118,145), inactivating p53 functions (158), inducing p21 CIP1/WAF1 mRNA transcription (2,24,33,89), and inhibiting apoptosis and DNA repair (87,104). Recent data have indicated that Tax can dramatically perturb mitotic regulation, causing micronuclei formation, cytokinesis failure, and chromosome instability (108,112,119).…”

Section: Introductionmentioning

confidence: 99%

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HTLV-1 Tax Effects on Cellular Mitotic Regulation

Merling¹

2007

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The human T-cell leukemia virus 1 (HTLV-1) encodes the tax gene (transactivator encoded by the pX region) which is a potent activator of viral transcription and Nuclear , this cyclin-dependent kinase inhibitor may also play a role in tax-IRS.As part of the research presented in this dissertation, a collection of HTLV-1 tax point mutants were isolated that permit normal growth of S. cerevisiae. Similar to wild-type tax, many mutants (C23W, A108T, L159F, and L235F) transactivated both the HTLV long terminal repeat (LTR) and the NF-!B reporters. The V19M mutant preferentially activated NF-!B, but was attenuated in LTR activation. None of the mutants significantly elevated the levels of p21 CIP1/WAF1 and p27 KIP1 , indicating that dramatic Tax-induced surges in p21and p27 KIP1 occurs by mechanisms distinct from NF-!B and LTR activation. Importantly, the ability of these mutants to activate APC was attenuated or abrogated. These data show that Tax-induced rapid senescence is causally associated with APC activation and suggest iv that the mitotic abnormalities that are associated with premature APC activation might play an important role in cell transformation by Tax.In a parallel study, we demonstrate that Tax interacts with both centrosomal Nek2-associated protein 1 (C-Nap1), a large coiled-coil protein that maintains centrosome cohesion, and protein phosphatase 1 (PP1) and that these interactions localize to the centrosome. Furthermore, in cells expressing tax, C-Nap1 phosphorylation is greatly diminished. C-Nap1 phosphorylation status plays an important role in centrosome cycle progression; PP1-mediated dephosphorylation of C-Nap1 maintains centriolar cohesion during interphase, and never in mitosis A (NIMA)-related kinase 2 (Nek2A)-mediated phosphorylation of C-Nap1 during G2/M triggers C-Nap1 dissociation from duplicated centrosomes permitting normal centrosome disjunction. Our data suggest that Tax, through recruitment of PP1 to C-Nap1, may permit prolonged C-Nap1 dephosphorylation thereby disrupting normal centrosome disjunction leading to observed Tax-induced centrosome abnormalities and distinct microtubule organizing center (MTOC) loss.Our studies have revealed two distinct pathways through which Tax could contribute to oncogenesis. First, our Tax mutants that retained LTR and NF-!B activation properties but were impaired in APC activation were also defective in the ability to transform Rat1 fibroblasts. Therefore, premature APC activation by Tax appears to correlate with the ability of Tax to induce cellular transformation. Second, our demonstration of Tax-mediated alterations in C-Nap1 phosphorylation cycle offers an explanation for the centrosome abnormalities and mitotic apparatus defects observed in response to Tax expression.Chromosomal abnormalities resulting from such mitotic apparatus defects may be expected to contribute to the oncogenic potential of Tax.v

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“…Tax induces phosphorylation of p53 and represses its transcriptional activity [11]. Tax affects INK proteins, through direct binding and suppression of p16-INK4A, transcriptional repression of p18-INK4C, decreased transcription of p19-INK4D, and increased expression of p21 [12,13]. In addition, Tax binds cyclindependent kinase-4 and cyclin D2, resulting in activation, enhanced phosphorylation of cyclin D3, and enhanced transcription of the cyclin D2 gene [5•,14-16].…”

Section: Pathogenesismentioning

confidence: 99%

Human T cell lymphotropic virus-associated leukemia/lymphoma

Ratner

2005

Current Opinion in Oncology

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Purpose of review-This article summarizes the current pathophysiologic basis for human T cell lymphotropic virus-associated leukemia/lymphoma as well as past, present, and future therapeutic options.Recent findings-New studies have been published on allogeneic stem cell transplantation, arsenic trioxide, and bortezomib for this condition.Summary-Studies of the molecular biology of human T cell lymphotropic virus-1-induced T cell leukemia/lymphoma have defined a critical role for oncoprotein, Tax, and activation of nuclear factor κB transcription pathways, which have provided rational approaches to improved therapy for T cell leukemia/lymphoma as well as a model for other hematopoietic malignancies characterized by nuclear factor κB activation.

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Human T‐cell leukemia virus type 1 Tax activates cyclin‐dependent kinase inhibitor p21/Waf1/Cip1 expression through a p53‐independent mechanism: Inhibition of cdk2

Cited by 25 publications

References 64 publications

Molecular mechanisms of cellular transformation by HTLV-1 Tax

Molecular mechanisms of cellular transformation by HTLV-1 Tax

HTLV-1 Tax Effects on Cellular Mitotic Regulation

Human T cell lymphotropic virus-associated leukemia/lymphoma

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