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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

04/19/2012

Pubmed ID

22510478

Pubmed Central ID

PMC3433748

DOI

10.1111/j.1474-9726.2012.00827.x

Scopus ID

2-s2.0-84863992349   46 Citations

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.

Author List

Kim G, Meriin AB, Gabai VL, Christians E, Benjamin I, Wilson A, Wolozin B, Sherman MY

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Line
Cellular 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
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a