STAT-1 Interacts with p53 to Enhance DNA Damage-induced Apoptosis

Townsend, Paul A.; Scarabelli, Tiziano M.; Davidson, Sean M.; Knight, Richard; Latchman, David S.; Stephanou, Anastasis

doi:10.1074/jbc.m302637200

Cited by 210 publications

(209 citation statements)

References 38 publications

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“…This is interesting since STAT-1 activation leads to antiproliferative and proapoptotic events in some cell types [38][39][40]. Likewise, islets or purified beta cells isolated from STAT1 −/− mice are resistant to IL-1β+IFN-γ-induced cell death (C. Geysemans, L. Ladriere, H. Callewaert, J. Rasschaert, D. Flamez, D. E. Levy, P. Matthys, D. L. Eizirik and C. Mathieu, submitted for publication).…”

Section: Discussionmentioning

confidence: 99%

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

et al. 2005

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Aims/hypothesis: It is thought that enterovirus infections initiate or facilitate the pathogenetic processes leading to type 1 diabetes. Exposure of cultured human islets to cytolytic enterovirus strains kills beta cells after a protracted period, suggesting a role for secondary virusinduced factors such as cytokines. Methods: To clarify the molecular mechanisms involved in virus-induced beta cell destruction, we analysed the global pattern of gene expression in human islets. After 48 h, RNA was extracted from three independent human islet preparations infected with coxsackievirus B5 or exposed to interleukin 1β (50 U/ml) plus interferon γ (1,000 U/ml), and gene expression profiles were analysed using Affymetrix HG-U133A gene chips, which enable simultaneous analysis of 22,000 probe sets. Results: As many as 13,077 genes were detected in control human islets, and 945 and 1293 single genes were found to be modified by exposure to viral infection and the indicated cytokines, respectively. Four hundred and eighty-four genes were similarly modified by the cytokines and viral infection. Conclusions/ interpretation: The large number of modified genes observed emphasises the complex responses of human islet cells to agents potentially involved in insulitis. Notably, both cytokines and viral infection significantly (p<0.02) increased the expression of several chemokines, the cytokine IL-15 and the intercellular adhesion molecule ICAM-1, which might contribute to the homing and activation of mononuclear cells in the islets during infection and/or an early autoimmune response. The present results provide novel insights into the molecular mechanisms involved in viral-and cytokine-induced human beta cell dysfunction and death.

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Section: Discussionmentioning

confidence: 99%

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

et al. 2005

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“…We previously showed that inhibition of STAT1 activation blocks p53-dependent cell cycle arrest by fludarabine*, 4 and Townsend et al 3,16 showed that STAT1 and p53 cooperate together in induction of apoptosis. These results led us to raise the question of STAT1 activation by genotoxic agents.…”

Section: Resultsmentioning

confidence: 99%

“…Since STAT1 and p53 may interact with each other, 3,4 we wanted to assess the role of p53 protein in STAT1 activation by genotoxic agents. Figure 3a shows that Dx did not induce Y701-STAT1 phosphorylation in HL60 or in Jurkat cells, two p53-null cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its transcriptional activity, p53 interacts directly or indirectly with other transcription factors such as c-myc, the nuclear factor kappa B (NF-kB) subunit RelA 2 or STAT1 (signal transducer and activator of transcription 1). 3,4 It is noteworthy that both STAT1 and p53 share various target genes involved in cell cycle arrest or in apoptosis such as p21 5 and CD95. 6 The cytotoxic activity of p53 inducers such as fludarabine* is increased by STAT1 transcriptional activation.…”

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confidence: 99%

“…4 Physical interaction between STAT1 and p53 is associated with a negative regulation of MDM2 expression and with an increase in p53 activation. 3 STAT1 is essential for signalling by interferons (IFNs). IFNg is a specific activator of STAT1, resulting in its phosphorylation on tyrosine 701 (pY701-STAT1) and on serine 727 (pS727-STAT1).…”

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confidence: 99%

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Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents

et al. 2007

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Chemotherapeutic drugs such as fludarabine*, doxorubicin or cisplatin are very potent activators of the anti-oncogene p53. Convergent studies suggest that p53 and STAT1 (signal transducer and activator of transcription 1) cooperate in the induction of cell death. We show that these drugs are also activators of STAT1 in p53-expressing cells, but not in p53-null cells. STAT1 activation was obtained in the presence of both the secretion inhibitor brefeldine A and the inhibitor of RNA synthesis, actinomycin D. p53-dependent STAT1 activation was reversed by overexpression of MDM2 and siRNAs against p53. Genetic analysis of p53 showed that expression of transcriptionally inactive p53 punctual mutants markedly increased Y701-STAT1 phosphorylation, and suggests that the p53 DNA-binding domain was alternatively involved in STAT1 activation or p53 multimerization. Immunoprecipitation experiments showed that ataxia telangiectasia mutated, p53, STAT1 and c-Abl1 (Abelson murine leukaemia viral oncogene homologue 1) were associated together. Treatment of cells with the c-Abl1 tyrosine kinase inhibitor STI571 decreased STAT1 activation by genotoxic drugs. Finally, genotoxic agents sensitized cells in response to very low doses of both interferon a and c (IFNa and c). These results show that genotoxic drugs induce STAT1 activation, an effect that depends on p53 protein but not on p53 transcriptional activity, and point to a novel pathway of STAT1 activation by genotoxic drugs, with involvement of c-Abl1 tyrosine kinase in sensitizing cells to IFN response.

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A genome‐wide siRNA screen for regulators of tumor suppressor p53 activity in human non‐small cell lung cancer cells identifies components of the RNA splicing machinery as targets for anticancer treatment

et al. 2017

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Reinstating wild‐type tumor suppressor p53 activity could be a valuable option for the treatment of cancer. To contribute to development of new treatment options for non‐small cell lung cancer (NSCLC), we performed genome‐wide siRNA screens for determinants of p53 activity in NSCLC cells. We identified many genes not previously known to be involved in regulating p53 activity. Silencing p53 pathway inhibitor genes was associated with loss of cell viability. The largest functional gene cluster influencing p53 activity was mRNA splicing. Prominent p53 activation was observed upon silencing of specific spliceosome components, rather than by general inhibition of the spliceosome. Ten genes were validated as inhibitors of p53 activity in multiple NSCLC cell lines: genes encoding the Ras pathway activator SOS1, the zinc finger protein TSHZ3, the mitochondrial membrane protein COX16, and the spliceosome components SNRPD3, SF3A3, SF3B1, SF3B6, XAB2, CWC22, and HNRNPL. Silencing these genes generally increased p53 levels, with distinct effects on CDKN1A expression, induction of cell cycle arrest and cell death. Silencing spliceosome components was associated with alternative splicing of MDM4 mRNA, which could contribute to activation of p53. In addition, silencing splice factors was particularly effective in killing NSCLC cells, albeit in a p53‐independent manner. Interestingly, silencing SNRPD3 and SF3A3 exerted much stronger cytotoxicity to NSCLC cells than to lung fibroblasts, suggesting that these genes could represent useful therapeutic targets.

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STAT-1 Interacts with p53 to Enhance DNA Damage-induced Apoptosis

Cited by 210 publications

References 38 publications

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents

A genome‐wide siRNA screen for regulators of tumor suppressor p53 activity in human non‐small cell lung cancer cells identifies components of the RNA splicing machinery as targets for anticancer treatment

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