title: Modulation of gene expression and tumor cell growth by redox modification of STAT3.
abstract: Reactive oxygen species (ROS) promote tumor cell proliferation and survival by directly modulating growth-regulatory molecules and key transcription factors. The signal transducer and activator of transcription 3 (STAT3) is constitutively active in a variety of tumor cell types, where the effect of ROS on the Janus kinase/STAT pathway has been examined. We report here that STAT3 is directly sensitive to intracellular oxidants. Oxidation of conserved cysteines by peroxide decreased STAT3 binding to consensus serum-inducible elements (SIE) in vitro and in vivo and diminished interleukin (IL)-6-mediated reporter expression. Inhibitory effects produced by cysteine oxidation in STAT3 were negated in redox-insensitive STAT3 mutants. In contrast, ROS had no effect on IL-6-induced STAT3 recruitment to the c-myc P2 promoter. Expression of a redox-insensitive STAT3 in breast carcinoma cells accelerated their proliferation while reducing resistance to oxidative stress. Our results implicate STAT3 in coupling intracellular redox homeostasis to cell proliferation and survival.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Shing-Hu
authors.initials: SH
authors.lastname: Cheung
authors.forename: Emma L
authors.initials: EL
authors.lastname: Evans
authors.forename: Peter E
authors.initials: PE
authors.lastname: Shaw
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D017124:Conserved Sequence; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D050794:STAT1 Transcription Factor / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013045:Species Specificity; D018183:Transplantation Chimera; D014714:Vertebrates
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D003545:Cysteine