UMMS Affiliation
Department of Cancer Biology and the Cancer Center
Publication Date
12-19-2007
Document Type
Article
Subjects
*Apoptosis; Caspases; *Cell Cycle; Cell Line, Tumor; Cell Survival; Chaperonin 60; Female; Gene Expression Regulation, Neoplastic; Humans; Microtubule-Associated Proteins; Mitochondria; Neoplasm Proteins; Neoplasms; Proteomics; RNA, Small Interfering; Tumor Suppressor Protein p53; bcl-2-Associated X Protein
Disciplines
Life Sciences | Medicine and Health Sciences
Abstract
Molecular chaperones may promote cell survival, but how this process is regulated, especially in cancer, is not well understood. Using high throughput proteomics screening, we identified the cell cycle regulator and apoptosis inhibitor survivin as a novel protein associated with the molecular chaperone Hsp60. Acute ablation of Hsp60 by small interfering RNA destabilizes the mitochondrial pool of survivin, induces mitochondrial dysfunction, and activates caspase-dependent apoptosis. This response involves disruption of an Hsp60-p53 complex, which results in p53 stabilization, increased expression of pro-apoptotic Bax, and Bax-dependent apoptosis. In vivo, Hsp60 is abundantly expressed in primary human tumors, as compared with matched normal tissues, and small interfering RNA ablation of Hsp60 in normal cells is well tolerated and does not cause apoptosis. Therefore, Hsp60 orchestrates a broad cell survival program centered on stabilization of mitochondrial survivin and restraining of p53 function, and this process is selectively exploited in cancer. Hsp60 inhibitors may function as attractive anticancer agents by differentially inducing apoptosis in tumor cells.
DOI of Published Version
10.1074/jbc.M705904200
Source
J Biol Chem. 2008 Feb 22;283(8):5188-94. Epub 2007 Dec 17. Link to article on publisher's site
Journal/Book/Conference Title
The Journal of biological chemistry
Related Resources
PubMed ID
18086682
Repository Citation
Ghosh, Jagadish C.; Dohi, Takehiko; Kang, Byoung; and Altieri, Dario C., "Hsp60 regulation of tumor cell apoptosis" (2007). Open Access Articles. 1936.
https://escholarship.umassmed.edu/oapubs/1936