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.
Mesh Terms:
Apoptosis, Apoptosis Regulatory Proteins, Breast Neoplasms, Carrier Proteins, Cell Division, DNA-Binding Proteins, Humans, Membrane Glycoproteins, Molecular Chaperones, Mutagenesis, Site-Directed, Mutation, Protein Isoforms, Stress, Physiological, TNF-Related Apoptosis-Inducing Ligand, Transcription Factors, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Apoptosis, Apoptosis Regulatory Proteins, Breast Neoplasms, Carrier Proteins, Cell Division, DNA-Binding Proteins, Humans, Membrane Glycoproteins, Molecular Chaperones, Mutagenesis, Site-Directed, Mutation, Protein Isoforms, Stress, Physiological, TNF-Related Apoptosis-Inducing Ligand, Transcription Factors, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Cancer Res.
Date: Jul. 15, 2003
PubMed ID: 12874020
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