RRC ID 54411
Author Oda T, Sekimoto T, Kurashima K, Fujimoto M, Nakai A, Yamashita T.
Title Acute HSF1 depletion induces cellular senescence through the MDM2-p53-p21 pathway in human diploid fibroblasts.
Journal J Cell Sci
Abstract Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, controls the expression of heat shock proteins (HSPs) as well as cell growth. Although acute depletion of HSF1 induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that HSF1 depletion-induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis but dependent on activation of the p53-p21 pathway, partly because of the increased expression of dehydrogenase/reductase 2 (DHRS2), a putative MDM2 inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, VER155008, an inhibitor of HSP70 family proteins, increased proteotoxicity and suppressed cell growth but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway resulting from reduced MDM2-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased DHRS2 expression contributes to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which HSF1 depletion-induced DHRS2 expression leads to activation of the MDM2-p53-p21 pathway required for HDIS.
Volume 131(9)
Published 2018-5-8
DOI 10.1242/jcs.210724
PII jcs.210724
PMID 29632240
MeSH Cell Line Cell Proliferation Cellular Senescence / physiology Diploidy Fibroblasts / cytology Fibroblasts / metabolism* HEK293 Cells HSP70 Heat-Shock Proteins / genetics HSP70 Heat-Shock Proteins / metabolism Heat Shock Transcription Factors / deficiency* Heat Shock Transcription Factors / metabolism Humans Proto-Oncogene Proteins c-mdm2 / genetics Proto-Oncogene Proteins c-mdm2 / metabolism* Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism*
IF 4.573
Times Cited 9
Resource
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)