Human T-cell leukemia virus type 1 Tax attenuates γ-irradiation-induced apoptosis through physical interaction with Chk2

Hu, Park Hyong; Sj, Jeong; Jeong, Jong Ju; Chung, JH; Jn, Brady

doi:10.1038/sj.onc.1209059

Cited by 34 publications

(32 citation statements)

References 57 publications

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“…Subsequently, Park et al (48) confirmed the binding of Tax to Chk2 and agreed with our suggestion that Tax impairs Chk2 function. However, these authors observed that Tax represses the kinase activity of Chk2, based on in vitro findings, as the model for impaired function (49). This result appears to conflict with our demonstration of Tax-mediated activation of endogenous Chk2 (26).…”

Section: Discussioncontrasting

confidence: 55%

Human T-cell Leukemia Virus Type 1 Tax Oncoprotein Prevents DNA Damage-induced Chromatin Egress of Hyperphosphorylated Chk2

Gupta¹,

Guo²,

Durkin

et al. 2007

Journal of Biological Chemistry

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De novo expression of human T-cell leukemia virus type 1 Tax results in cellular genomic instability. We demonstrated previously that Tax associates with the cell cycle check point regulator Chk2 and proposed that the inappropriate activation of Chk2 provides a model for Tax-induced loss of genetic integrity (Haoudi, A., Daniels, R. C., Wong, E., Kupfer, G., and Semmes, O. J. (2003) Human T-cell leukemia virus type 1 (HTLV-1) 3 is the causative agent of adult T-cell leukemia, a malignancy of CD4 ϩ T lymphocytes (1-4), and is also known to act in the etiology of a neurodegenerative disease, tropical spastic paraparesis/HTLV-1-associated myelopathy (5, 6). The mechanism of leukemogenesis or the neoplastic growth of HTLV-1-infected CD4 ϩ T-cells is incompletely understood. However, a preponderance of experimental data have established that the viral protein Tax is a crucial component in HTLV-1-mediated transformation.An overall increase in cellular genomic instability is thought to be a driving force behind carcinogenesis (7-9). Thus, it is not unexpected that HTLV-1-transformed lymphocytes demonstrate a range of chromosomal abnormalities. However, the observation that HTLV-1-infected but not -transformed T-cells also display significant genomic instability (10 -14) suggests that loss of genomic integrity is an event that predisposes the cell to change. More specifically, the observation that Tax expression alone results in genomic instability provides a compelling cause-effect model for the development of adult T-cell leukemia (12,15,16).Although Tax regulates a wide range of cellular functions, there is no evidence that Tax directly interacts with DNA in a manner that would result in DNA damage (11). Thus, most theories propose that Tax impairs the cellular DNA damage repair response, resulting in increased surviving mutation frequency (15,17,18). Possible molecular models include the repression of human telomerase (10) and ␤-polymerase (19), overactivation of proliferating cell nuclear antigen (20, 21), and persistence of unprotected DNA breaks (22). Additionally, Tax has been proposed to perturb the mitotic spindle checkpoint and to directly effect chromosomal segregation, resulting in aneuploidy (23). Another possible mechanism proposes that disruption in the cytokinesis nuclear division coordination is via premature activation of the anaphase-promoting complex achieved by binding of Tax to the anaphase-promoting complex-associated protein Cdc20 (24). In fact, a reasonable hypothesis is that cell cycle ablation, repair enzyme repression, and disruption in the regulation of cell division all contribute to genomic instability. Recently, in an elegant ex vivo approach, Sibon et al. (25) demonstrated that, early in infection, CD4 ϩ T-cells display striking genomic instability and cell cycle redistribution. These authors reported an increase in the number of HTLV-1-infected cells residing in G 2 /M phase, a result consistent with early observations in Tax-expressing cells (26 -28).We demonstrated previously that ...

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Section: Discussioncontrasting

confidence: 55%

Human T-cell Leukemia Virus Type 1 Tax Oncoprotein Prevents DNA Damage-induced Chromatin Egress of Hyperphosphorylated Chk2

Gupta¹,

Guo²,

Durkin

et al. 2007

Journal of Biological Chemistry

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“…Activation of ATM stimulates Chk2, which phosphorylates p53 on serine-20, disrupting its interaction with Mdm2 and stabilizing p53 protein in response to DNA damage (Shieh et al, 1997;Chehab et al, 2000b). HTLV-I Tax interacts with and inhibits functions of Chk1/Chk2 (Haoudi et al, 2003;Park et al, 2004Park et al, , 2006. It is well established that HTLV-I Tax oncoprotein inhibits the function of the tumor suppressor p53 protein, although the mechanism of p53 inactivation in HTLV-I biology is still debated (Grassmann et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells

Datta

Nicot

2007

Oncogene

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Persistent inhibition of telomerase induces a severe telomere shortening in human T-cell leukemia virus type-1-infected cells which signals a DNA double-strand break damage response, formation of telomere dysfunction-induced foci and activates the ATM pathway. In turn, activation of ATM and its downstream effectors led to an increased phosphorylation and acetylation on specific residues of p53 known to be involved in transcriptional activation. Disruption of Mdm2-p53 complexes coupled with increased proteasomal degradation of MDMX further enhanced reactivation of p53 transcription, ultimately leading to senescence of tumor cells. Induction of senescence in these T-cells was associated with an increased expression of p21, p16 and activation of GSK3b. Our results support the cancer-aging model and demonstrate that the halt of aging in cancer cells can be reversed through reactivation of p53.

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“…However, it was prematurely lost in Taxexpressing cells. Interestingly, Tax has also been shown to bind Chk2 (23,41). Although the effect of Tax binding on Chk2 kinase activity remains controversial, it has been proposed that Tax might alter the phosphorylation status of Chk2 and prevent its egress from chromatin (22).…”

Section: Vol 82 2008mentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Tax Attenuates the ATM-Mediated Cellular DNA Damage Response

Chandhasin

Ducu

Berkovich

et al. 2008

J Virol

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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.Preserving genomic integrity is critical for all living systems. The integrity and survival of a cell depend on the stability of its DNA. Damaged DNA is detected by cellular sensing systems, which activate specific DNA repair pathways. Malfunction of this repair network, collectively known as the DNA damage response, leads to DNA mutations, a subset of which can promote cellular transformation. Double-stranded DNA breaks (DSBs) arise from genotoxic insults and normal physiological processes such as DNA replication (24, 38). The mechanisms by which eukaryotic cells sense DNA breaks remain to be elucidated, but one of the earliest detectable events in DNA damage sensing is the activation of the ataxia telangiectasia mutated (ATM) kinase (45).ATM is a member of the PI3K-like kinase family and is mutated in ataxia telangiectasia patients (45). Immediately after exposure of cells to DSB-inducing agents such as ionizing radiation (IR) and radiomimetic drugs, changes in chromatin structure activate the intermolecular autophosphorylation of ATM on Ser1981, resulting in the dissociation of inactive ATM dimers into active monomers that allow substrate accessibility to the ATM kinase domain (2). ATM substrates include cellular targets such as NBS1, Chk2, p53, MDC1, histone 2AX (H2AX), and BRCA1, which are key players in the maintenance of genomic integrity (5,19,44,47). Some of these substrates are phosphorylated by ATM in the nucleoplasm, while others are phosphorylated at sites of DNA damage where ATM is recruited via interaction with the Mre11/Rad50/NBS1 (MRN) complex. At sites of DNA breaks within chromatin, the phosphorylation of H2AX and MDC1 by ATM establishes a positive-feedback loop that maintains ATM autophosphorylation and amplifies the DNA damage response (31). Genetic defects in crucial parts of this network lead to a grou...

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Human T-cell leukemia virus type 1 Tax attenuates γ-irradiation-induced apoptosis through physical interaction with Chk2

Cited by 34 publications

References 57 publications

Human T-cell Leukemia Virus Type 1 Tax Oncoprotein Prevents DNA Damage-induced Chromatin Egress of Hyperphosphorylated Chk2

Human T-cell Leukemia Virus Type 1 Tax Oncoprotein Prevents DNA Damage-induced Chromatin Egress of Hyperphosphorylated Chk2

Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells

Human T-Cell Leukemia Virus Type 1 Tax Attenuates the ATM-Mediated Cellular DNA Damage Response

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