Open AccessAcute HSF1 depletion induces cellular senescence through the MDM2-p53-p21 pathway in human diploid fibroblasts
Author(s) -
Tsukasa Oda,
Takayuki Sekimoto,
Kiminori Kurashima,
Mitsuaki Fujimoto,
Asami Nakai,
Takayuki Yamashita
Publication year - 2018
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.210724
Subject(s) - biology , hsf1 , microbiology and biotechnology , mdm2 , proteotoxicity , senescence , heat shock factor , heat shock , heat shock protein , hsp70 , apoptosis , genetics , gene , protein folding
Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, control of the expression of heat shock proteins (HSPs) and 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, 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 due to 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.