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 Kudoh, M. Articles by Reed, J. C. Search for Related Content PubMed PubMed Citation Articles by Kudoh, M. Articles by Reed, J. C.

Bag1 Proteins Regulate Growth and Survival of ZR-75-1 Human Breast Cancer Cells¹

The Burnham Institute, La Jolla, California 92037

Bag1 proteins bind heat shock protein M_r 70,000 (Hsp 70) family molecular chaperonesand regulate diverse pathways involved in cell proliferation, apoptosis, and stress responses. Four isoforms of Bag1 can be produced froma single gene in humans, including a nuclear-targeted long version (Bag1L)and a shorter cytosolic isoform (Bag1). Because overexpression of Bag1and Bag1L has been reported in breast cancers, we explored the effects of Bag1 and Bag1L on the growth of ZR-75-1 human breast cancer cells cultured in vitro and in tumor xenograft models using immunocompromised mice. Cells stably transfected with expression plasmids encoding either Bag1 or Bag1L displayed comparable rates of growth in cultures containing 10% serum, compared with control-transfected ZR-75-1 cells. In contrast, ZR-75-1 cells stably expressing mutants of Bag1 or Bag1L, which lack the COOH-terminal domain (C) required for heat shock protein M_r 70,000 binding, displayed retarded growth rates. When cultured without serum, the viability of control-transfected, as well as Bag1C- and Bag1LC-expressing, cells declined with time, whereas Bag1- and Bag1L-overexpressing ZR-75-1 cells survived for over a week in culture. Caspase protease activation induced by serum deprivation was also prevented by stable expression of either Bag1 or Bag1L in ZR-75-1 cells. In addition, sensitivity to anchorage dependence was restored partially in ZR-75-1 cells expressing dominant-negative Bag1C and Bag1LC. In tumor xenograft studies involving injection of ZR-75-1 cells into mammary fat pads of female nu/nu mice, ZR-75-1 cells expressing Bag1 or Bag1L formed 1.4–1.6-fold larger tumors compared with control-transfected cells, whereas tumors formed by Bag1C- and Bag1LC-expressing cells grew very slowly and reached sizes < one-third of tumors generated by Neo-control ZR-75-1 cells. Altogether, these findings demonstrate that Bag1 and Bag1L provoke similar changes in breast cancer cell growth and survival and suggest that interference with Bag1 or Bag1L function might be a useful strategy for opposing breast cancer.

This article has been cited by other articles:

				E. Bjorling, C. Lindskog, P. Oksvold, J. Linne, C. Kampf, S. Hober, M. Uhlen, and F. Ponten A Web-based Tool for in Silico Biomarker Discovery Based on Tissue-specific Protein Profiles in Normal and Cancer Tissues Mol. Cell. Proteomics, May 1, 2008; 7(5): 825 - 844. [Abstract] [Full Text] [PDF]

				D. R. Hostetter, C. R. K. Loeb, F. Chu, and C. S. Craik Hip Is a Pro-survival Substrate of Granzyme B J. Biol. Chem., September 21, 2007; 282(38): 27865 - 27874. [Abstract] [Full Text] [PDF]

				D. G Morris, M. Musat, S. Czirjak, Z. Hanzely, D. M Lillington, M. Korbonits, and A. B Grossman Differential gene expression in pituitary adenomas by oligonucleotide array analysis Eur. J. Endocrinol., July 1, 2005; 153(1): 143 - 151. [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]

				R. Sasson, E. Rimon, A. Dantes, T. Cohen, V. Shinder, A. Land-Bracha, and A. Amsterdam Gonadotrophin-induced gene regulation in human granulosa cells obtained from IVF patients. Modulation of steroidogenic genes, cytoskeletal genes and genes coding for apoptotic signalling and protein kinases Mol. Hum. Reprod., May 1, 2004; 10(5): 299 - 311. [Abstract] [Full Text] [PDF]

				H. Doong, K. Rizzo, S. Fang, V. Kulpa, A. M. Weissman, and E. C. Kohn CAIR-1/BAG-3 Abrogates Heat Shock Protein-70 Chaperone Complex-mediated Protein Degradation: ACCUMULATION OF POLY-UBIQUITINATED Hsp90 CLIENT PROTEINS J. Biol. Chem., August 1, 2003; 278(31): 28490 - 28500. [Abstract] [Full Text] [PDF]

				P. A. Townsend, R. I. Cutress, A. Sharp, M. Brimmell, and G. Packham BAG-1 Prevents Stress-induced Long-term Growth Inhibition in Breast Cancer Cells via a Chaperone-dependent Pathway Cancer Res., July 15, 2003; 63(14): 4150 - 4157. [Abstract] [Full Text] [PDF]

				M. Guzey, S. Kitada, and J. C. Reed Apoptosis Induction by 1{alpha},25-Dihydroxyvitamin D3 in Prostate Cancer Mol. Cancer Ther., July 1, 2002; 1(9): 667 - 677. [Abstract] [Full Text] [PDF]