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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-07-2132. This Article Full Text (PDF) All Versions of this Article: 2002-07-2132v1 101/6/2393    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Villunger, A. Articles by Strasser, A. Search for Related Content PubMed PubMed Citation Articles by Villunger, A. Articles by Strasser, A. Social Bookmarking                   What's this? Submitted July 18, 2002 Accepted October 31, 2002 Essential role for the BH3-only protein Bim, but redundant roles for Bax, Bcl-2, and Bcl-w in the control of granulocyte survival Andreas Villunger, Clare Scott, Philippe Bouillet, and Andreas Strasser* Molecular Genetics of Cancer, The Walter and Eliza Hall Institute for Medical Research, Melbourne, VIC, Australia * Corresponding author; email: strasser{at}wehi.edu.au. Programmed cell death of granulocytes is one of the mechanisms that limit inflammatory responses. Members of the Bcl-2 protein family are essential regulators of apoptosis induced by growth factor withdrawal or cytotoxic stress. We have used gene-targeted and transgenic mice to investigate the roles of the pro-survival molecules Bcl-2 and Bcl-w and their pro-apoptotic relatives Bax and Bim in spontaneous and stress-induced apoptosis of granulocytes from bone marrow or the peritoneum. Bim-deficiency, like Bcl-2 overexpression, rendered granulocytes resistant to cytokine withdrawal and cytotoxic drugs but absence of Bax alone had no protective effect. Loss of Bcl-2 or Bcl-w did not increase the sensitivity of granulocytes to any of these apoptotic stimuli but Bcl-2 was essential for the in vitro survival of myeloid progenitors under conditions of cytokine-withdrawal where cell death was mediated, in part, by Bim. G-CSF, a key survival factor for granulocytes, enhanced viability of cells lacking bcl-2, bcl-w, bax or bim, indicating that none of these genes alone is the essential target of this cytokines pro-survival function. Expression analysis of pro-apoptotic Bcl-2 family members in granulocytes revealed that the BH3-only protein Bmf is induced upon cytokine-withdrawal. These results indicate that the BH3-only protein Bim and possibly also Bmf are critical initiators of spontaneous and drug-induced apoptosis of granulocytes whereas Bcl-2, Bcl-w and Bax act in a redundant manner in regulating granulocyte survival and death, respectively. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. C. Reed Bcl-2-family proteins and hematologic malignancies: history and future prospects Blood, April 1, 2008; 111(7): 3322 - 3330. [Abstract] [Full Text] [PDF] M. Ekoff, T. Kaufmann, M. Engstrom, N. Motoyama, A. Villunger, J.-I. Jonsson, A. Strasser, and G. Nilsson The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells Blood, November 1, 2007; 110(9): 3209 - 3217. [Abstract] [Full Text] [PDF] L. Coultas, S. Terzano, T. Thomas, A. Voss, K. Reid, E. G. Stanley, C. L. Scott, P. Bouillet, P. Bartlett, J. Ham, et al. 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