Document Detail


Prevention of cytokine withdrawal-induced apoptosis by Mcl-1 requires interaction between Mcl-1 and Bim.
MedLine Citation:
PMID:  20921992     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
Growth factor withdrawal from hemopoietic cells results in activation of the mitochondrial pathway of apoptosis. Members of the Bcl-2 family regulate this pathway, with anti-apoptotic members counteracting the effects of pro-apoptotic members. We investigated the effect on Mcl-1 function of mutation at a conserved threonine 163 residue (T163) in its proline, glutamate, serine, and threonine rich (PEST) region. Under normal growth conditions, Mcl-1 half-life increased with alteration of T163 to glutamic acid, but decreased with mutation to alanine. However, both T163 mutants exhibited greater pro-survival effects compared with the wild type, which can be explained by an increased stability of the T163A mutant in cytokine-starved conditions. Both the mutant forms exhibited prolonged binding to pro-apoptotic Bim in cytokine-deprived cells. The extent to which Mcl-1 mutants were able to exert their anti-apoptotic effects correlated with their ability to associate with Bim. We further observed that primary bone marrow derived macrophages survived following cytokine withdrawal as long as Bim and Mcl-1 remained associated. In our study, we were unable to detect a role for GSK-3-mediated regulation of Mcl-1 expression. Based on these results we propose that upon cytokine withdrawal, survival of hemopoietic cells depends on association between Mcl-1 and Bim. Furthermore, alteration of T163 of Mcl-1 may change the protein such that its association with Bim is affected, resulting in prolonged association and increased survival.
Authors:
Sarwat Jamil; Shih Wei Wang; Lise Bondy; Shadi Mojtabavi; Vincent Duronio
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry and cell biology = Biochimie et biologie cellulaire     Volume:  88     ISSN:  1208-6002     ISO Abbreviation:  Biochem. Cell Biol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-05     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8606068     Medline TA:  Biochem Cell Biol     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  809-18     Citation Subset:  IM    
Affiliation:
Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada.
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MeSH Terms
Descriptor/Qualifier:
Grant Support
ID/Acronym/Agency:
MOP-74481//Canadian Institutes of Health Research

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