Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence

Kuo, Yu‐Liang; Giam, Chou-Zen

doi:10.1038/sj.emboj.7601054

Cited by 90 publications

(177 citation statements)

References 36 publications

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“…The fate of these cells would therefore be dependent on the pleiotropic activities of this viral protein, which dysregulates the transcription of genes involved in cellular proliferation, cell cycle control, apoptosis, and rapid senescence, mainly through the constitutive activation of the NF-B pathway (14,24,41). Thus, these Taxexpressing cells might either undergo programmed cell death or survive and/or proliferate.…”

Section: Discussionmentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Wencker

Sausse

Derse

et al. 2007

J Virol

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The human pre-T-cell receptor alpha (TCR␣; pT␣) gene encodes a polypeptide which associates with the TCR␤ chain and CD3 molecules to form the pre-TCR complex. The surface expression of the pre-TCR is pT␣ dependent, and signaling through this complex triggers an early ␣␤ T-cell developmental checkpoint inside the thymus, known as ␤-selection. E2A transcription factors, which are involved at multiple stages of T-cell development, regulate the transcription of the pT␣ gene. Here we show that the regulatory protein Tax of the human T-cell leukemia virus type 1 (HTLV-1) efficiently suppresses the E47-mediated activation of the pT␣ promoter. Furthermore, we report that in Tax lentivirally transduced human MOLT-4 T cells, which constitutively express the pT␣ gene, the amount of pT␣ transcripts decreases. Such a decrease is not observed in MOLT-4 cells transduced by a vector encoding the Tax mutant K88A, which is unable to interact with p300. These data underline that Tax inhibits pT␣ transcription by recruiting this coactivator. Finally, we show that the expression of Tax in human immature thymocytes results in a decrease of pT␣ gene transcription but does not modify the level of E47 transcripts. These observations indicate that Tax, by silencing E proteins, down-regulates pT␣ gene transcription during early thymocyte development. They further provide evidence that Tax can interfere with an important checkpoint during T-cell differentiation in the thymus.

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Section: Discussionmentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Wencker

Sausse

Derse

et al. 2007

J Virol

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“…Several reports indeed demonstrated that Tax-expressing cells undergo ATM/ATRdependent cell cycle delay in S-G 2 phases, G 1 arrest, and senescence because of a surge of p21 Waf1/Cip1 expression, or even apoptosis. [36][37][38][39][40] Although these observations appear contradictory with the ability of Tax to speed up S phase progression, several lines of evidence suggest that pro-mitotic and antiproliferative activities have to be considered as interconnected processes. Indeed, the ATM/ATR-dependent phosphorylation of H2AX in Tax-expressing cells suggests that unscheduled activation of replication origins creates replicative lesions that alarm the DDR machinery.…”

Section: Discussionmentioning

confidence: 99%

Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

Boxus

Twizere

Legros

et al. 2012

Blood

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The 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 IntroductionHuman T-cell leukemia virus-1 (HTLV-1) is a retrovirus that infects approximately 20 million people worldwide. 1 Although the majority of infected people remain lifelong asymptomatic carriers, 2% to 5% develop either adult T-cell leukemia (ATL) or chronic inflammatory diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis. 1 Two major hallmarks of HTLV-1-infected cells are: preferential proliferation compared with normal lymphocytes 2 and tendency to accumulate genomic lesions, a prerequisite for oncogenesis. 3,4 Although the molecular mechanisms underlying T-cell transformation remain to be elucidated, it is generally accepted that the virally encoded Tax protein plays a central role. Tax indeed displays pleiotropic activities that cooperate to drive cell cycle progression and perturb genome stability. 4,5 For example, Tax shortens G 1 phase and accelerates transition into S phase by manipulating positive and negative G 1 phase regulators (ie, cyclin D/CDK complex, Rb and CDK inhibitors). [6][7][8] In addition, Tax is thought to indirectly generate DNA damage by suppressing DNA repair processes and competing with cellular DNA damage response (DDR). 4,5 Recent data also support a direct role for Tax-induced reactive oxygen species in the occurrence of DNA lesions. 9 Conceptually, Tax activities are achieved through proteinprotein interactions in both nuclear and cytoplasmic cellular compartments. 10 In the nucleus, Tax accumulates within foci called Tax speckled structures (TSS), 11 which overlap with the cellular machinery required for transcription, splicing, post-transcriptional modifications of proteins, DNA repair, and checkpoint control. 12 In this report, we further demonstrate that Tax recruits the MCM2-7 replicative helicase within the TSS and modulates the program of replication origin firing. Notably, this mechanism favors cell cycle progression and directly compromises genome stability. Methods Plasmids, antibodies, yeast 2-hybrid, and GST pulldownSee supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Cell cultureHeLa, Rat-1, and 293GP2 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and 2mM l-glutamine and penicillin/ streptomycin. Jurkat, HUT78 and JPX9 (Jurkat cell lines stably transfected either with tax-1 gene driven by a metallothionein-inducible promoter) were kept in RPMI 1640 supplemented with 10% FBS, 2mM l-glutamine, and penicillin/streptomycin. Expression of the viral protein was induced in JPX9 cells by adding 120 M zinc chloride...

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“…Examples of the pleiotropic effects of Tax on host cells include potent nuclear factor kappa B (NF-!B) activation (26,82,178,187,192,194) and cell cycle perturbation (90,96,108,111,112,118,145). Tax has been shown to activate the expression of interleukin-2 (IL-2), IL-2R", IL-3, IL-4, granulocyte-macrophage colony stimulating factor, proliferating cell nuclear antigen (PCNA), transforming growth factor beta (TGF-#), mimentin, proenkephalin, egr-1 (Krox20), egr-2 (Krox24), fra-1, c-fos, c-myc, c-sis, bcl-xL, c-Jun, JunB and JunD (105).…”

Section: Overview Of Htlv Taxmentioning

confidence: 99%

“…In essence, Tax activates the cellular program for mitotic exit far in advance of its normal schedule. Tax-induced APC is often accompanied by severe mitotic abnormalities associated with the premature loss of cyclin A, cyclin B1, securin, and Skp2, the substrate targeting subunit of SCF Skp2 , another E3 ubiquitin ligase (96,97). Importantly, the loss of Skp2 renders SCF inactive and dramatically stabilizes its substrate, p27 KIP1 , the major G1/S cyclin-dependent kinases inhibitors (CKI).…”

Section: Tax Effects On Apcmentioning

confidence: 99%

“…Recent data from our laboratory suggest that a loss of SIC1p, the inhibitor of S. cerevisiae G1/S cyclin-dependent kinase, prevents Tax-induced arrest. Importantly, a loss of p27 KIP1 function is a common feature of HTLV-1 transformed human T-cells that constitutively express Tax (96). In this dissertation, the yeast system is utilized to investigate the mechanisms by which Tax perturbs the cell cycle.…”

Section: Hypothesis and Rationalementioning

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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Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence

Cited by 90 publications

References 36 publications

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

HTLV-1 Tax Effects on Cellular Mitotic Regulation

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