The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype. Aging Cell 2012 Aug;11(4):617-27
Date
04/19/2012Pubmed ID
22510478Pubmed Central ID
PMC3433748DOI
10.1111/j.1474-9726.2012.00827.xScopus ID
2-s2.0-84863992349 (requires institutional sign-in at Scopus site) 63 CitationsAbstract
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.
Author List
Kim G, Meriin AB, Gabai VL, Christians E, Benjamin I, Wilson A, Wolozin B, Sherman MYAuthor
Ivor J. Benjamin MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell LineCellular Senescence
DNA Damage
DNA-Binding Proteins
Down-Regulation
ELAV Proteins
Feedback, Physiological
Fibroblasts
Heat Shock Transcription Factors
Heat-Shock Response
Humans
NF-kappa B
Signal Transduction
Sirtuin 1
Transcription Factors
Werner Syndrome
p38 Mitogen-Activated Protein Kinases
