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.

Rights and Permissions

Citation: J Biol Chem. 2008 Feb 22;283(8):5188-94. Epub 2007 Dec 17. Link to article on publisher's site

DOI of Published Version

10.1074/jbc.M705904200

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of biological chemistry

PubMed ID

18086682

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