This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Townsend, P. A. Articles by Packham, G. Search for Related Content PubMed PubMed Citation Articles by Townsend, P. A. Articles by Packham, G.

BAG-1 Prevents Stress-induced Long-term Growth Inhibition in Breast Cancer Cells via a Chaperone-dependent Pathway¹

Cancer Research UK Oncology Unit, Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton S016 6YD, United Kingdom

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.

This article has been cited by other articles:

				N. K. Clemo, T. J. Collard, S. L. Southern, K. D. Edwards, M. Moorghen, G. Packham, A. Hague, C. Paraskeva, and A. C. Williams BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-{kappa}B activity Carcinogenesis, April 1, 2008; 29(4): 849 - 857. [Abstract] [Full Text] [PDF]

				E. V. Doukhanina, S. Chen, E. van der Zalm, A. Godzik, J. Reed, and M. B. Dickman Identification and Functional Characterization of the BAG Protein Family in Arabidopsis thaliana J. Biol. Chem., July 7, 2006; 281(27): 18793 - 18801. [Abstract] [Full Text] [PDF]

				J. Liman, S. Ganesan, C. P. Dohm, S. Krajewski, J. C. Reed, M. Bahr, F. S. Wouters, and P. Kermer Interaction of BAG1 and Hsp70 Mediates Neuroprotectivity and Increases Chaperone Activity Mol. Cell. Biol., May 1, 2005; 25(9): 3715 - 3725. [Abstract] [Full Text] [PDF]

				P. A Townsend, R. I. Cutress, C. J. Carroll, K. M. Lawrence, T. M. Scarabelli, G. Packham, A. Stephanou, and D. S. Latchman BAG-1 Proteins Protect Cardiac Myocytes from Simulated Ischemia/Reperfusion-induced Apoptosis via an Alternate Mechanism of Cell Survival Independent of the Proteasome J. Biol. Chem., May 14, 2004; 279(20): 20723 - 20728. [Abstract] [Full Text] [PDF]