TY - JOUR
T1 - Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13
AU - Liu, Junli
AU - Xia, Hongguang
AU - Kim, Minsu
AU - Xu, Lihua
AU - Li, Ying
AU - Zhang, Lihong
AU - Cai, Yu
AU - Norberg, Helin Vakifahmetoglu
AU - Zhang, Tao
AU - Furuya, Tsuyoshi
AU - Jin, Minzhi
AU - Zhu, Zhimin
AU - Wang, Huanchen
AU - Yu, Jia
AU - Li, Yanxia
AU - Hao, Yan
AU - Choi, Augustine
AU - Ke, Hengming
AU - Ma, Dawei
AU - Yuan, Junying
N1 - Funding Information:
We thank Dan Finley, Bruce Yankner, Zhujun Yao, Dana Christofferson, Dimitry Ofengeim, and Bénédicte Py for comments on the manuscript; Dr. Xin Xie of the National Center for Drug Screening in Shanghai for help with the original compound screen for autophagy regulators; Dr. Wade Harper for providing expression vectors of USP10 and USP13; Dr. Zhenkun Lou for mutant expression vector for USP10; Dr. Caroline Shamu (the director of the ICCB screening facility); and David Wrobel and Stewart Rudnicki for helps with siRNA screening. This work was supported in part by a NIH Director's Pioneer Award US (to J.Y.), grants from the Chinese Academy of Sciences (KGCX2-SW-209 and KJCX2-YW-H08 [to D.M.]), the National Natural Science Foundation of China (21020102037 [to D.M.], and 90813007 [to L.Z.]) and the National Institute on Aging US (R37 AG012859 and PO1 AG027916 [to J.Y.]). M.K. is a recipient of Samsung Scholarship from South Korea. H.V.N. is supported in part by a fellowship form the Swedish Society for Medical Research (SSMF).
PY - 2011/9/30
Y1 - 2011/9/30
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2011.08.037
DO - 10.1016/j.cell.2011.08.037
M3 - Article
C2 - 21962518
AN - SCOPUS:80053501671
VL - 147
SP - 223
EP - 234
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1
ER -