Document Detail


Regulation of calpain activity by c-Myc through calpastatin and promotion of transformation in c-Myc-negative cells by calpastatin suppression.
MedLine Citation:
PMID:  18544539     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Maryam Niapour; Yongmao Yu; Stuart A Berger
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-06-10
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-07-28     Completed Date:  2008-09-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21371-81     Citation Subset:  IM    
Affiliation:
Arthritis and Immune Disorder Research Centre, University Health Network and the Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Acrylates / 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:
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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