Journal of Cell Science, Vol 112, Issue 11 1771-1783, Copyright © 1999 by Company of Biologists

JOURNAL ARTICLES

Developmental regulation of Bcl-2 family protein expression in the involuting mammary gland

AD Metcalfe, A Gilmore, T Klinowska, J Oliver, AJ Valentijn, R Brown, A Ross, G MacGregor, JA Hickman and CH Streuli
School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.

Epithelial cells within the mammary gland undergo developmental programmes of proliferation and apoptosis during the pregnancy cycle. After weaning, secretory epithelial cells are removed by apoptosis. To determine whether members of the Bcl-2 gene family could be involved in regulating this process, we have examined whether changes in their expression occur during this developmental apoptotic program in vivo. Bax and Bcl-x were evenly expressed throughout development. However, expression of Bak and Bad was increased during late pregnancy and lactation, and the proteins were present during the time of maximal apoptotic involution. Thereafter, their levels declined. In contrast, Bcl-w was expressed in pregnancy and lactation but was downregulated at the onset of apoptosis. Bcl-2 was not detected in lactating or early involuting mammary gland. Thus, the pro-apoptotic proteins Bax, Bak and Bad, as well as the death-suppressors Bcl-x, Bcl-2 and Bcl-w, are synthesised in mouse mammary gland, and dynamic changes in the expression profiles of these proteins occurs during development. To determine if changes in Bak and Bcl-w expression could regulate mammary apoptosis, their effect on cultured mouse mammary epithelial cells was examined in transient transfection assays. Enforced expression of Bak induced rapid mammary apoptosis, which could be suppressed by coexpression of Bcl-w. In extracts of mammary tissue in vivo, Bak heterodimerized with Bcl-x whereas Bax associated with Bcl-w, but Bak/Bcl-w heterodimers were not detected. Thus, Bak and Bcl-w may regulate cell death through independent pathways. These results support a model in which mammary epithelial cells are primed for apoptosis during the transition from pregnancy to lactation by de novo expression of the death effectors Bak and Bad. It is suggested that these proteins are prevented from triggering apoptosis by anti-apoptotic Bcl-2 family proteins until involution, when the levels of Bcl-w decline. Our study provides evidence that regulated changes in the expression of cell death genes may contribute to the developmental control of mammary apoptosis.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				E. L. Annen, C. M. Stiening, B. A. Crooker, A. C. Fitzgerald, and R. J. Collier Effect of continuous milking and prostaglandin E2 on milk production and mammary epithelial cell turnover, ultrastructure, and gene expression J Anim Sci, May 1, 2008; 86(5): 1132 - 1144. [Abstract] [Full Text] [PDF]

				A. J. Brennan, J. A. Sharp, C. Lefevre, D. Topcic, A. Auguste, M. Digby, and K. R. Nicholas The Tammar Wallaby and Fur Seal: Models to Examine Local Control of Lactation J Dairy Sci, June 1, 2007; 90(13_suppl): E66 - E75. [Abstract] [Full Text] [PDF]

				P. Wang, A. P. Gilmore, and C. H. Streuli Bim Is an Apoptosis Sensor That Responds to Loss of Survival Signals Delivered by Epidermal Growth Factor but Not Those Provided by Integrins J. Biol. Chem., October 1, 2004; 279(40): 41280 - 41285. [Abstract] [Full Text] [PDF]

				K. A. Green, M. J. Naylor, E. T. Lowe, P. Wang, E. Marshman, and C. H. Streuli Caspase-mediated Cleavage of Insulin Receptor Substrate J. Biol. Chem., June 11, 2004; 279(24): 25149 - 25156. [Abstract] [Full Text] [PDF]

				J. P. Bailey, K. M. Nieport, M. P. Herbst, S. Srivastava, R. A. Serra, and N. D. Horseman Prolactin and Transforming Growth Factor-{beta} Signaling Exert Opposing Effects on Mammary Gland Morphogenesis, Involution, and the Akt-Forkhead Pathway Mol. Endocrinol., May 1, 2004; 18(5): 1171 - 1184. [Abstract] [Full Text] [PDF]

				P. Wang, A. J. Valentijn, A. P. Gilmore, and C. H. Streuli Early Events in the Anoikis Program Occur in the Absence of Caspase Activation J. Biol. Chem., May 23, 2003; 278(22): 19917 - 19925. [Abstract] [Full Text] [PDF]

				S. Ha, S. Lee, M. Chung, and Y. Choi Mouse ING1 Homologue, a Protein Interacting with A1, Enhances Cell Death and Is Inhibited by A1 in Mammary Epithelial Cells Cancer Res., March 1, 2002; 62(5): 1275 - 1278. [Abstract] [Full Text] [PDF]

				E. Tonner, M. C. Barber, G. J. Allan, J. Beattie, J. Webster, C. B. A. Whitelaw, and D. J. Flint Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice Development, January 10, 2002; 129(19): 4547 - 4557. [Abstract] [Full Text] [PDF]

				H. Zhang, W. Holzgreve, and C. De Geyter Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway Hum. Mol. Genet., October 1, 2001; 10(21): 2329 - 2339. [Abstract] [Full Text] [PDF]

				W. Yan, M. Samson, B. Jégou, and J. Toppari Bcl-w Forms Complexes with Bax and Bak, and Elevated Ratios of Bax/Bcl-w and Bak/Bcl-w Correspond to Spermatogonial and Spermatocyte Apoptosis in the Testis Mol. Endocrinol., May 1, 2000; 14(5): 682 - 699. [Abstract] [Full Text]

				A. P. Gilmore, A. D. Metcalfe, L. H. Romer, and C. H. Streuli Integrin-Mediated Survival Signals Regulate the Apoptotic Function of Bax through Its Conformation and Subcellular Localization J. Cell Biol., April 17, 2000; 149(2): 431 - 446. [Abstract] [Full Text] [PDF]

				A. Nguyen and J. Pollard Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution Development, January 7, 2000; 127(14): 3107 - 3118. [Abstract] [PDF]