BAG-1 prevents stress-induced long-term growth inhibition in breast cancer cells via a chaperone-dependent pathway.
BAG-1 is a multifunctional protein that interacts with a wide range of cellular targets. There is accumulating evidence that overexpression of BAG-1 may play an important role in breast cancer; however, the functional consequences of BAG-1 expression and its mechanism of action in breast cancer cells have not been studied in detail. Here we demonstrate that BAG-1 overexpression completely protected breast cancer cells from apoptosis and long-term growth inhibition induced by heat shock and also partially protected cells from other stresses, including hypoxia, radiation, and chemotoxic drugs. BAG-1 exists as three protein isoforms, and all isoforms prevented stress-induced growth inhibition. This required a conserved lysine in the BAG-1S ubiquitin-like domain thought to be important for proteasome binding and COOH-terminal amino acids required for interaction with the chaperone molecules, Hsc70 and Hsp70. Although expression of BAG-1 was unaltered by heat shock, endogenous and overexpressed BAG-1S relocalized from the cytoplasm to the nucleus after heat shock. The endogenous BAG-1S.Hsc70/Hsp70 complex dissociated after heat shock but was maintained at a detectable level in cells overexpressing BAG-1S. BAG-1-mediated resistance to stress-induced growth inhibition is likely to have a major impact on the development and response to therapy of breast cancer. Targeting the interaction of BAG-1 with chaperones is an attractive strategy to counter the biological effects of BAG-1.
Townsend
Paul A
PA
Cancer Research UK Oncology Unit, Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton S016 6YD, United Kingdom.
Cutress
Ramsey I
RI
Sharp
Adam
A
Brimmell
Matthew
M
Packham
Graham
G
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D018832:Molecular Chaperones / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020033:Protein Isoforms; D013312:Stress, Physiological / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha