Document Detail

HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins.
MedLine Citation:
PMID:  19179333     Owner:  NLM     Status:  MEDLINE    
4-Hydroxynonenal (HNE) is a pro-apoptotic electrophile generated during the spontaneous decomposition of oxidized lipids. We have previously shown that HNE activates the transcription factor, heat shock factor 1 (HSF1), and promotes cytoprotective heat shock gene expression and that silencing HSF1 sensitizes the colon cancer cell line RKO to HNE-induced apoptosis. Here we report a reduction in the anti-apoptotic proteins Bcl-X(L), Mcl-1, and Bcl-2 in HSF1-silenced RKO cells, and we examine the underlying mechanism. To investigate the regulation of the Bcl-2 family by HSF1, microarray analysis of gene expression was performed. We observed that the Hsp70 co-chaperone, BAG3 (Bcl-2-associated athanogene domain 3), is strongly induced by HNE in control but not in HSF1-silenced colon cancer cells. Silencing BAG3 expression with small interfering RNA caused a dramatic reduction in Bcl-X(L), Mcl-1, and Bcl-2 protein levels in colon cancer cells and increased apoptosis, similar to the effect of silencing HSF1. Also, immunoprecipitation experiments indicate specific interactions between BAG3, Hsp70, and the Bcl-2 family member, Bcl-X(L). Overall, our data reveal that BAG3 is HSF1-inducible and has a unique role facilitating cancer cell survival during pro-apoptotic stress by stabilizing the level of Bcl-2 family proteins.
Aaron T Jacobs; Lawrence J Marnett
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-01-29
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-03-30     Completed Date:  2009-06-01     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9176-83     Citation Subset:  IM    
Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
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MeSH Terms
Adaptor Proteins, Signal Transducing / genetics,  metabolism*
Aldehydes / pharmacology*
Apoptosis / drug effects
Cell Line
DNA-Binding Proteins / genetics,  metabolism*
Gene Expression Regulation / drug effects
Oligonucleotide Array Sequence Analysis
Protein Binding
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism*
RNA, Small Interfering / genetics
Transcription Factors / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Aldehydes; 0/DNA-Binding Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Small Interfering; 0/Transcription Factors; 0/myeloid cell leukemia sequence 1 protein; 29343-52-0/4-hydroxy-2-nonenal

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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