HSF1 Regulates Cellular Senescence: Role of the DHRS2-MDM2-p53 Pathway
Heat shock transcription factor 1 (HSF1) regulates lifespan, age-related pathologies and cancer development. These functions of HSF1 have mainly been attributed to the maintenance of proteostasis by activating the expression of heat shock protein (Hsp) ge
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Abstract Introduction Heat shock transcription factor 1 (HSF1) regulates lifespan, age-related pathologies and cancer development. These functions of HSF1 have mainly been attributed to the maintenance of proteostasis by activating the expression of heat shock protein (Hsp) genes. However, increasing attention has been attracted to non-canonical functions of HSF1 linked to cell proliferation and metabolism through the regulation of diverse non-Hsp genes. In here, I aim to describe experimental evidence that the DHRS2-MDM2-p53 pathway mediates HSF1 depletion-induced cellular senescence (HDIS) and to discuss the potential significance of this finding in tumorigenesis and aging. Methods The author reviewed relevant papers of the DHRS2-MDM2-p53 pathway and HDIS, focusing on tumorigenesis and aging. Results Acute depletion of HSF1 induced cellular senescence in human diploid fibroblasts. Several lines of evidence indicated that HDIS is mediated by activation of the DHRS2-MDM2-p53 pathway but not through decreased expression of Hsp or increased proteotoxic stress. Accumulating evidence in literature suggests that DHRS2 is an important regulator of tumorigenesis, underlying the above findings. In addition, there is substantial evidence that HSF1 regulates cellular senescence through multiple pathways. Conclusions To better understand the molecular mechanisms of HDIS and its in vivo functions will provide new insights into roles of HSF1 in tumorigenesis and aging and effects of HSF1-targeting therapies.
T. Yamashita (*) Laboratory of Molecular Genetics, The Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. A. Asea, P. Kaur (eds.), Heat Shock Proteins, https://doi.org/10.1007/7515_2020_17
T. Yamashita
Keywords Aging · Cancer · Cellular senescence · DHRS2 · Heat shock transcription factor 1 · MDM2-p53 pathway
Abbreviations CDK2 DHRS2 DOX HDF HDIS HSF1 Hsp Mieap NAMPT PGC1α ROS SASP SA-β-gal shRNA SDR TERT
cyclin dependent kinase 2 dehydrogenase/reductase 2 doxycycline human diploid fibroblast HSF1 depletion-induced cellular senescence heat shock transcription factor 1 heat shock protein mitochondria-eating protein nicotinamide phosphoribosyltransferase peroxisome proliferator-activated receptor γ coactivator-1α reactive oxygen species senescence-associated secretory phenotype senescence-associated β-galactosidase short-hairpin RNA short-chain NAD/NADP-dependent dehydrogenase/reductase telomerase reverse transcriptase
1 Introduction Heat shock transcription factor 1 (HSF1) activates the expression of heat shock protein (Hsp) genes in response to proteotoxic stress and, thereby, maintains proteostasis [1]. In an orthodox view, prominent phenotypes of HSF1-deficient organisms, such as shortened life-span, acceleration of age-related neurodegeneration, and tumor suppression, are explained by the accumulation of misfolded protein aggregates [1]. However, accumulating findings reveal that HSF1 functions in more extensive b
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