期刊
CELL
卷 147, 期 1, 页码 223-234出版社
CELL PRESS
DOI: 10.1016/j.cell.2011.08.037
关键词
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资金
- NIH US
- Chinese Academy of Sciences [KGCX2-SW-209, KJCX2-YW-H08]
- National Natural Science Foundation of China [21020102037, 90813007]
- National Institute on Aging US [R37 AG012859, PO1 AG027916]
- Samsung Scholarship from South Korea
- Swedish Society for Medical Research (SSMF)
Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named spautin-1 for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.
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