title: Ras-induced ROS upregulation affecting cell proliferation is connected with cell type-specific alterations of HSF1/SESN3/p21Cip1/WAF1 pathways.
abstract: Oncogenes of the RAS family regulate many of the cell's activities, including proliferation, survival and differentiation. Activating mutations in these genes are common events for many types of cancer. One of the contradictory points concerning the biological significance of Ras activation is its dual effect (pro- or anti-proliferative) on cell reproduction. One of mechanisms by which Ras proteins influence cell growth is a regulation of intracellular level of reactive oxygen species (ROS), second messengers affecting variety of cellular processes including cell proliferation. Recently it was shown that repression of SESN1 and SESN3 genes, whose protein products control regeneration of peroxiredoxins, can play a critical role in Ras-induced ROS upregulation. In the present study we have found that Ras-induced repression of SESN3 expression and ROS upregulation is mediated via the modifications of transcriptional activity of HSF1. Interestingly, mutant Ras overexpression altered the activity of HSF1 in opposite directions in different cell contexts, in particular in human normal fibroblasts and HaCaT immortalized keratinocytes, but these opposite changes caused similar repression of SESN3 expression followed by elevation of ROS content and inhibition of cell proliferation in corresponding cell types. The inhibitory effect on cell proliferation was mediated by upregulation of p21(Cip1/WAF1). Thus, HSF1/SESN3/ROS/p21(Cip1/WAF1)-mediated deceleration of cell growth may contribute to cell defense systems protecting the organism from excessive proliferation of cells that overexpress activated Ras oncoproteins.
authors: Institute of Carcinogenesis, Russian Blokhin Cancer Research Center, Moscow, Russia.
authors: Maria
authors: M
authors: Zamkova
authors: Natalia
authors: N
authors: Khromova
authors: Boris P
authors: BP
authors: Kopnin
authors: Pavel
authors: P
authors: Kopnin
mesh_terms: D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005453:Fluorescence; D017930:Genes, Reporter; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007700:Kinetics; D050505:Mutant Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014161:Transduction, Genetic; D015854:Up-Regulation / Q000235:genetics; D000084622:Sestrins
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D050505:Mutant Proteins; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014157:Transcription Factors; C493956:CDKN1A protein, human; C000619706:HSF1 protein, human; C485523:SESN3 protein, human; D000084622:Sestrins; C501009:HRAS protein, human
keywords: HSF1; ROS; Ras; SESN3; cell growth
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