The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype.

[werner syndrome]

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 p 53 -p 21 and p 38 -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 Hsf 1 . This inhibition in large part resulted from the downregulation of SIRT 1 , 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 Hsf 1 further activates the p 38 -NF-ÎºB-SASP pathway , which in turn promotes senescence . Overexpression of Hsf 1 inhibited the p 38 -NFÎºB-SASP pathway and partially relieved senescence . Therefore , downregulation of Hsf 1 plays an important role in the development or in the maintenance of DNA damage signaling-induced cell senescence .

Diseases
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Diseases presenting "large part" symptom

child syndrome

congenital toxoplasmosis

werner syndrome

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