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Title: Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration
Authors: He, M.Y.
Xu, S.B.
Qu, Z.H.
Guo, Y.M.
Liu, X.C.
Cong, X.X.
Wang, J.F.
Low, B.C. 
Li, L.
Wu, Q.
Lin, P.
Yan, S.G.
Bao, Z.
Zhou, Y.T.
Zheng, L.L.
Keywords: cellular senescence
heat-shock protein
muscle regeneration
skeletal muscle
Issue Date: 2019
Publisher: Blackwell Publishing Ltd
Citation: He, M.Y., Xu, S.B., Qu, Z.H., Guo, Y.M., Liu, X.C., Cong, X.X., Wang, J.F., Low, B.C., Li, L., Wu, Q., Lin, P., Yan, S.G., Bao, Z., Zhou, Y.T., Zheng, L.L. (2019). Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration. Aging Cell 18 (5) : e13003. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Cellular senescence plays both beneficial and detrimental roles in embryonic development and tissue regeneration, while the underlying mechanism remains elusive. Recent studies disclosed the emerging roles of heat-shock proteins in regulating muscle regeneration and homeostasis. Here, we found that Hsp90?, but not Hsp90? isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90?-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90? in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90? preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90? interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90? in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90? in regulating p53 stability to suppress senescence both in vitro and in vivo. © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Source Title: Aging Cell
ISSN: 1474-9718
DOI: 10.1111/acel.13003
Rights: Attribution 4.0 International
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