Hsp90β interacts with MDM2 to suppress p53‐dependent senescence during skeletal muscle regeneration
| Autor: | Li Ling Zheng, Xiao Xia Cong, Shui Bo Xu, Yue Mei Guo, Yi Ting Zhou, Zhang Bao, Li Li, Qiang Wu, Jian Feng Wang, Shi Gui Yan, Min Yi He, Xiao Ceng Liu, Zi Hao Qu, Peng Lin, Boon Chuan Low |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Senescence p53 Aging senescence Hsp90β Cell Line 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation MDM2 medicine Myocyte cellular senescence Animals HSP90 Heat-Shock Proteins skeletal muscle Muscle Skeletal heat‐shock protein Gene knockdown muscle regeneration biology Regeneration (biology) Skeletal muscle Proto-Oncogene Proteins c-mdm2 Cell Biology Original Articles Ubiquitin ligase Cell biology 030104 developmental biology medicine.anatomical_structure biology.protein Mdm2 Original Article Tumor Suppressor Protein p53 030217 neurology & neurosurgery |
| Zdroj: | Aging Cell |
| ISSN: | 1474-9726 1474-9718 |
| Popis: | 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 Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA‐seq analysis disclosed a transcriptional elevation of p21 in Hsp90β‐depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53‐dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild‐type p53 and modulated its degradation via a proteasome‐dependent manner. Moreover, Hsp90β 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 Hsp90β 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 Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo. |
| Databáze: | OpenAIRE |
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