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    Hsp60 regulation of tumor cell apoptosis

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    Authors
    Ghosh, Jagadish C.
    Dohi, Takehiko
    Kang, Byoung
    Altieri, Dario C.
    UMass Chan Affiliations
    Department of Cancer Biology and the Cancer Center
    Document Type
    Journal Article
    Publication Date
    2007-12-19
    Keywords
    *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
    Life Sciences
    Medicine and Health Sciences
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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.
    Source
    J Biol Chem. 2008 Feb 22;283(8):5188-94. Epub 2007 Dec 17. Link to article on publisher's site
    DOI
    10.1074/jbc.M705904200
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/39121
    PubMed ID
    18086682
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M705904200
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    UMass Chan Faculty and Researcher Publications

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