Document Detail

Regulation of heat-induced apoptosis by Mcl-1 degradation and its inhibition by Hsp70.
MedLine Citation:
PMID:  19148187     Owner:  NLM     Status:  MEDLINE    
Cellular stress eliminates irreversibly damaged cells by initiating the intrinsic death pathway. Cell stress is sensed by pro- and antiapoptotic members of the Bcl-2 protein family, which regulate the release of apoptogenic factors, such as cytochrome c, from mitochondria. Exposure of cells to hyperthermia results in the activation of the proapoptotic Bcl-2 family protein Bax, which plays an essential role in cytochrome c release. Heat directly affects Bax activity in vitro; however, antiapoptotic Bcl-2 family proteins, such as Bcl-xL, can suppress this activation, suggesting that a second heat-sensitive step must be breached before apoptosis ensues in cells exposed to hyperthermia. Here we show that heat shock causes the loss of Mcl-1 protein. Depletion of Noxa by short hairpin RNA protected cells from hyperthermia by preventing Mcl-1 degradation. Heat shock caused the dissociation of Noxa from Mcl-1, which allowed binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1 ubiquitination and degradation. Overexpression of Hsp70, which prevents heat-induced Bax activation, stabilized Mcl-1 protein levels in heat-shocked cells. This resulted from reduced Mule binding and ubiquitination as well as enhanced Mcl-1 expression compared with cells without Hsp70. Our results demonstrate that loss of Mcl-1 is a critical heat-sensitive step leading to Bax activation that is controlled by Hsp70.
A R Stankiewicz; A M Livingstone; N Mohseni; D D Mosser
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-01-16
Journal Detail:
Title:  Cell death and differentiation     Volume:  16     ISSN:  1476-5403     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-03-16     Completed Date:  2009-05-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  638-47     Citation Subset:  IM    
Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.
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MeSH Terms
Apoptosis / genetics,  physiology*
Cell Line
Cell Line, Tumor
Cell Survival / genetics
HSP70 Heat-Shock Proteins / genetics,  metabolism*
Hot Temperature*
Protein Binding / genetics
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*,  genetics,  metabolism*
RNA Interference
Ubiquitin-Protein Ligases / genetics,  metabolism
bcl-2-Associated X Protein / genetics,  metabolism
Reg. No./Substance:
0/HSP70 Heat-Shock Proteins; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2-Associated X Protein; 0/myeloid cell leukemia sequence 1 protein; EC protein, human; EC Ligases

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