期刊
CANCER CELL
卷 27, 期 6, 页码 864-876出版社
CELL PRESS
DOI: 10.1016/j.ccell.2015.05.004
关键词
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资金
- Canadian Stem Cell Network
- Leukemia and Lymphoma Society
- NIH [NCI 1R01CA157456]
- Canadian Institutes of Health Research
- Terry Fox Research Foundation Program Project Group Grant
- MaRS Innovation
- Ontario Institute for Cancer Research
- Ontario Ministry of Research and Innovation
- Princess Margaret Cancer Centre Foundation
- Ministry of Long Term Health and Planning in the Province of Ontario
- CIHR
From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.
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