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PMID:18086682
| Citation |
Ghosh, JC, Dohi, T, Kang, BH and Altieri, DC (2008) Hsp60 regulation of tumor cell apoptosis. J. Biol. Chem. 283:5188-94 |
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| 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. |
| Links |
PubMed Online version:10.1074/jbc.M705904200 |
| Keywords |
Apoptosis/genetics; Caspases/genetics; Caspases/metabolism; Cell Cycle/genetics; Cell Line, Tumor; Cell Survival; Chaperonin 60/antagonists & inhibitors; Chaperonin 60/genetics; Chaperonin 60/metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins/biosynthesis; Microtubule-Associated Proteins/genetics; Mitochondria/genetics; Mitochondria/metabolism; Mitochondria/pathology; Neoplasm Proteins/biosynthesis; Neoplasm Proteins/genetics; Neoplasms/genetics; Neoplasms/metabolism; Neoplasms/pathology; Proteomics; RNA, Small Interfering/genetics; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; bcl-2-Associated X Protein/genetics; bcl-2-Associated X Protein/metabolism |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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