title: Transcriptional regulation of gene expression during osmotic stress responses by the mammalian target of rapamycin.
abstract: Although stress can suppress growth and proliferation, cells can induce adaptive responses that allow them to maintain these functions under stress. While numerous studies have focused on the inhibitory effects of stress on cell growth, less is known on how growth-promoting pathways influence stress responses. We have approached this question by analyzing the effect of mammalian target of rapamycin (mTOR), a central growth controller, on the osmotic stress response. Our results showed that mammalian cells exposed to moderate hypertonicity maintained active mTOR, which was required to sustain their cell size and proliferative capacity. Moreover, mTOR regulated the induction of diverse osmostress response genes, including targets of the tonicity-responsive transcription factor NFAT5 as well as NFAT5-independent genes. Genes sensitive to mTOR-included regulators of stress responses, growth and proliferation. Among them, we identified REDD1 and REDD2, which had been previously characterized as mTOR inhibitors in other stress contexts. We observed that mTOR facilitated transcription-permissive conditions for several osmoresponsive genes by enhancing histone H4 acetylation and the recruitment of RNA polymerase II. Altogether, these results reveal a previously unappreciated role of mTOR in regulating transcriptional mechanisms that control gene expression during cellular stress responses.
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Ortells
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morancho
authors.forename: Katherine
authors.initials: K
authors.lastname: Drews-Elger
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Keith R
authors.initials: KR
authors.lastname: Laderoute
authors.forename: Cristina
authors.initials: C
authors.lastname: López-Rodríguez
authors.forename: Jose
authors.initials: J
authors.lastname: Aramburu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D009997:Osmotic Pressure; D013312:Stress, Physiological / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; C469992:Ddit4 protein, mouse; D050778:NFATC Transcription Factors; D014157:Transcription Factors; D058570:TOR Serine-Threonine Kinases; D012321:DNA-Directed RNA Polymerases