| Prevention of cytokine withdrawal-induced apoptosis by Mcl-1 requires interaction between Mcl-1 and Bim. | |
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MedLine Citation:
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PMID: 20921992 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sarwat Jamil; Shih Wei Wang; Lise Bondy; Shadi Mojtabavi; Vincent Duronio |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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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:
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Created Date: 2010-10-05 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8606068 Medline TA: Biochem Cell Biol Country: Canada |
Other Details:
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Languages: eng Pagination: 809-18 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada. |
Export Citation:
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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MOP-74481//Canadian Institutes of Health Research |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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