title: The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype.
abstract: Heat shock response (HSR) that protects cells from proteotoxic stresses is downregulated in aging, as well as upon replicative senescence of cells in culture. Here we demonstrate that HSR is suppressed in fibroblasts from the patients with segmental progerioid Werner Syndrome, which undergo premature senescence. Similar suppression of HSR was seen in normal fibroblasts, which underwent senescence in response to DNA damaging treatments. The major DNA-damage-induced signaling (DDS) pathways p53-p21 and p38-NF-kB-SASP contributed to the HSR suppression. The HSR suppression was associated with inhibition of both activity and transcription of the heat shock transcription factor Hsf1. This inhibition in large part resulted from the downregulation of SIRT1, which in turn was because of decrease in the expression of the translation regulator HuR. Importantly, we uncovered a positive feedback regulation, where suppression of Hsf1 further activates the p38-NF-κB-SASP pathway, which in turn promotes senescence. Overexpression of Hsf1 inhibited the p38-NFκB-SASP pathway and partially relieved senescence. Therefore, downregulation of Hsf1 plays an important role in the development or in the maintenance of DNA damage signaling-induced cell senescence.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Geunwon
authors.initials: G
authors.lastname: Kim
authors.forename: Anatoli B
authors.initials: AB
authors.lastname: Meriin
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Gabai
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Christians
authors.forename: Ivor
authors.initials: I
authors.lastname: Benjamin
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilson
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Sherman
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D051959:ELAV Proteins / Q000378:metabolism; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014898:Werner Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051959:ELAV Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D016328:NF-kappa B; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1