title: Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents.
abstract: 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 alpha and gamma (IFNalpha and gamma). 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.
authors.affiliation: Centre National de la Recherche Scientifique, UMR CNRS 6101, Faculté de Médecine de Limoges, Université de Limoges, CHU Dupuytren, Laboratoire d'Hématologie, Limoges, France.
authors.forename: I
authors.initials: I
authors.lastname: Youlyouz-Marfak
authors.forename: N
authors.initials: N
authors.lastname: Gachard
authors.forename: C
authors.initials: C
authors.lastname: Le Clorennec
authors.forename: I
authors.initials: I
authors.lastname: Najjar
authors.forename: F
authors.initials: F
authors.lastname: Baran-Marszak
authors.forename: L
authors.initials: L
authors.lastname: Reminieras
authors.forename: E
authors.initials: E
authors.lastname: May
authors.forename: G W
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: R
authors.initials: R
authors.lastname: Fagard
authors.forename: J
authors.initials: J
authors.lastname: Feuillard
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D020126:Brefeldin A / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D007372:Interferons / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D020126:Brefeldin A; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D007372:Interferons; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D016315:Proto-Oncogene Proteins c-abl; D014740:Vidarabine; C024352:fludarabine; D002945:Cisplatin