| Regulation of calpain activity by c-Myc through calpastatin and promotion of transformation in c-Myc-negative cells by calpastatin suppression. | |
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MedLine Citation:
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PMID: 18544539 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The c-Myc transcription factor is commonly dysregulated in cancer. c-Myc also sensitizes cells to apoptosis induced by a variety of toxic events. c-Myc turnover is rapid and mediated by the proteasome and intracellular calpains. Therefore, c-Myc accumulation could contribute to cell death associated with protease inhibitors. We investigated the response of c-Myc-positive and c-Myc-negative rat fibroblast cells to proteasome and calpain inhibitors. Apoptosis induced by the proteasome inhibitor, epoxomycin, was c-Myc-independent, whereas apoptosis induced by the calpain inhibitor, PD150606, or by knockdown of calpain small subunit 1 (CPNS1) was strongly dependent on c-Myc. HL60 cells knocked down for c-Myc expression exhibited reduced calpain activity and decreased sensitivity to PD150606 but not epoxomycin. Calpain inhibitor- or CPNS1 knockdown-induced apoptosis in c-Myc-positive fibroblasts was associated with cell detachment and could be prevented by plating cells on fibronectin, suggesting an anoikis phenomenon. c-Myc stimulated calpain activity by suppressing calpastatin expression, the endogenous calpain inhibitor. Knockdown of calpastatin in c-Myc-negative cells led to a restoration of calpain activity, enhanced cell growth, cell cycle redistribution, anchorage independence, and tumorigenicity in immunodeficient mice. Taken together, these results indicate that c-Myc regulates calpain activity through calpastatin; apoptosis induced by calpain inhibition is dependent on c-Myc, and calpastatin knockdown promotes transformation in c-Myc-negative cells. |
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Authors:
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Maryam Niapour; Yongmao Yu; Stuart A Berger |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-06-10 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 283 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-07-28 Completed Date: 2008-09-22 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 21371-81 Citation Subset: IM |
Affiliation:
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Arthritis and Immune Disorder Research Centre, University Health Network and the Department of Immunology, University of Toronto, Toronto, Ontario, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acrylates
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pharmacology Animals Apoptosis Calcium-Binding Proteins / metabolism* Calpain / chemistry* Cell Adhesion Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Fibroblasts / metabolism Fibronectins / metabolism HL-60 Cells Humans Proto-Oncogene Proteins c-myc / metabolism* RNA, Small Interfering / metabolism Rats |
| Chemical | |
Reg. No./Substance:
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0/Acrylates; 0/Calcium-Binding Proteins; 0/Enzyme Inhibitors; 0/Fibronectins; 0/PD 150606; 0/Proto-Oncogene Proteins c-myc; 0/RNA, Small Interfering; 79079-11-1/calpastatin; EC 3.4.22.-/Calpain |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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