| HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins. | |
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MedLine Citation:
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PMID: 19179333 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Aaron T Jacobs; Lawrence J Marnett |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-01-29 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-03-30 Completed Date: 2009-06-01 Revised Date: 2010-09-23 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 9176-83 Citation Subset: IM |
Affiliation:
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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. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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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 | |
ID/Acronym/Agency:
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P01ES013125/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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