Regulating BRCA1 protein stability by cathepsin S-mediated ubiquitin degradation
- 주제(기타) Biochemistry & Molecular Biology; Cell Biology
- 설명문(일반) [Kim, SeoYoung; Jin, Hee; Lee, Yun-Sil] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 120750, South Korea; [Seo, Hang-Rhan] Inst Pasteur Korea, Funct Morphometry 2, Seongnam Si 463400, Gyeonggi Do, South Korea; [Lee, Hae June] Korea Inst Radiol & Med Sci, Div Basic Radiat Biosci, Seoul 139706, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published, hybrid
- 발행기관 NATURE PUBLISHING GROUP
- 발행년도 2019
- URI http://www.dcollection.net/handler/ewha/000000160195
- 본문언어 영어
- Published As http://dx.doi.org/10.1038/s41418-018-0153-0
- PubMed https://pubmed.ncbi.nlm.nih.gov/30006610
초록/요약
Cathepsin S (CTSS) is a cysteine protease that is thought to play a role in many physiological and pathological processes including tumor growth, angiogenesis, and metastasis; it has been identified as a radiation response gene. Here, we examined the role of CTSS in regulating the DNA damage response in breast cancer cells. Activating CTSS (producing the cleavage form of the protein) by radiation induced proteolytic degradation of BRCA1, which ultimately suppressed DNA double-strand break repair activity. Depletion of CTSS by RNAi or expression of a mutant type of CTSS enhanced the protein stability of BRCA1 by inhibiting its ubiquitination. CTSS interacted with the BRCT domain of BRCA1 and facilitated ubiquitin-mediated proteolytic degradation of BRCA1, which was tightly associated with decreased BRCA1-mediated DNA repair activity. Treatment with a pharmacological CTSS inhibitor inhibited proteolytic degradation of BRCA1 and restored BRCA1 function. Depletion of CTSS by shRNA delayed tumor growth in a xenograft mouse model, only in the presence of functional BRCA1. Spontaneously uced rat mammary tumors and human breast cancer tissues with high levels of CTSS expression showed low BRCA1 expression. From these data, we suggest that CTSS inhibition is a good strategy for functional restoration of BRCA1 in breast cancers with reduced BRCA1 protein stability.
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