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BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation

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Author(s)
Seung Un SeoSeon Min WooSeul Gi LeeMin Yeong KimHyun Shik LeeYung Hyun ChoiSang Hyun KimYoung-Chae ChangKyoung-jin MinTaeg Kyu Kwonag
Keimyung Author(s)
Kwon, Taeg Kyu
Department
Dept. of Immunology (면역학)
Journal Title
Redox Biol
Issued Date
2022
Volume
53
Keyword
OdanacatibBaxp53Sp1BAP1Mitochondrial ROS
Abstract
Cathepsin K inhibitor (odanacatib; ODN) and cathepsin K knockdown (siRNA) enhance oxaliplatin-induced apoptosis through p53-dependent Bax upregulation. However, its underlying mechanisms remain unclear. In this study, we elucidated the mechanism behind enhancement of oxaliplatin-induced apoptosis by ODN. We also investigated the molecular mechanisms of ODN-induced Bax upregulation. Here, we demonstrated that ODN-induced Bax upregulation required p53, but it was independent of p53 transcriptional activity. Various mutants of the DNA-binding domain of p53 induced Bax upregulation in ODN-treated cells. p53 functional domain analysis showed that the C-terminal domain of p53 participates in the physical interaction and stabilization of Sp1, a major transcription factor of Bax. We screened a specific siRNA encoding 50 deubiquitinases and identified that BAP1 stabilizes Sp1. The knockdown or catalytic mutant form of BAP1 abolished the ODN-induced upregulation of Sp1 and Bax expression. Mechanistically, ODN induced BAP1 phosphorylation and enhanced Sp1-BAP1 interaction, resulting in Sp1 ubiquitination and degradation. Interestingly, ODN-induced BAP1 phosphorylation and DNA damage were modulated by the production of mitochondrial reactive oxygen species (ROS). Mitochondrial ROS scavengers prevented DNA damage, BAP1-mediated Sp1 stabilization, and Bax upregulation by ODN. BAP1 downregulation by siRNA inhibited apoptosis induced by the combined treatment of ODN and oxaliplatin/etoposide. Therefore, Sp1 is a crucial transcription factor for ODN-induced Bax upregulation, and Sp1 stabilization is regulated by BAP1.
Keimyung Author(s)(Kor)
권택규
Publisher
School of Medicine (의과대학)
Citation
Seung Un Seo et al. (2022). BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation. Redox Biol, 53, 102336. doi: 10.1016/j.redox.2022.102336
Type
Article
ISSN
2213-2317
Source
https://www.sciencedirect.com/science/article/pii/S2213231722001082
DOI
10.1016/j.redox.2022.102336
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/44345
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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