HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 27, 25158-25165, July 4, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/27/25158    most recent M212849200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haughn, L. Articles by Hockenbery, D. M. Search for Related Content PubMed PubMed Citation Articles by Haughn, L. Articles by Hockenbery, D. M. Social Bookmarking                      What's this?

BCL-2 and BCL-X_L Restrict Lineage Choice during Hematopoietic Differentiation^*

Loralee Haughn  , Robert G. Hawley ¶, Deborah K. Morrison ||, Harald von Boehmer  and David M. Hockenbery  **

From the Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, the ^¶Hematopoiesis Department, Jerome H. Holland Laboratory, American Red Cross, Rockville, Maryland 20855, the ^||Cellular Growth Mechanisms Section, NCI-Frederick Cancer Research & Development Center, National Institutes of Health, Frederick, Maryland 21702, and the Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Differentiation of hematopoietic cells from multipotential progenitors is regulated by multiple growth factors and cytokines. A prominent feature of these soluble factors is promotion of cell survival, in part mediated by expression of either of the anti-apoptotic proteins, BCL-2 and BCL-X_L. The complex expression pattern of these frequently redundant survival factors during hematopoiesis may indicate a role in lineage determination. To investigate the latter possibility, we analyzed factor-dependent cell-Patersen (FDCP)-Mix multipotent progenitor cells in which we stably expressed BCL-2 or BCL-X_L. Each factor maintained complete survival of interleukin-3 (IL-3)-deprived FDCP-Mix cells but, unexpectedly, directed FDCP-Mix cells along restricted and divergent differentiation pathways. Thus, IL-3-deprived FDCP-Mix BCL-2 cells differentiated exclusively to granulocytes and monocytes/macrophages, whereas FDCP-Mix BCL-X_L cells became erythroid. FDCP-Mix BCL-2 cells grown in IL-3 were distinguished from FDCP-Mix and FDCP-Mix BCL-X_L cells by a striking reduction in cellular levels of Raf-1 protein. Replacement of the BCL-2 BH4 domain with the related BCL-X_L BH4 sequence resulted in a switch of FDCP-Mix BCL-2 cells to erythroid fate accompanied by persistence of Raf-1 protein expression. Moreover, enforced expression of Raf-1 redirected FDCP-Mix BCL-2 cells to an erythroid fate, and prohibited generation of myeloid cells. These results identify novel roles for BCL-2 and BCL-X_L in cell fate decisions beyond cell survival. These effects are associated with differential regulation of Raf-1 expression, perhaps involving the previously identified interaction between BCL-2-BH4 and the catalytic domain of Raf-1.

Received for publication, December 17, 2002 , and in revised form, April 24, 2003.

^* This work was supported by National Institutes of Health Grant IP50HL54881 (to D. M. H.) and by a Cancer Research Institute fellow-ship (to L. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D2–190, 1100 Fairview Ave. N., Seattle, WA 98109. Tel.: 206-667-4611; Fax: 206-667-6519; E-mail: dhockenb{at}fhcrc.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. Garcon, C. Rivat, C. James, C. Lacout, V. Camara-Clayette, V. Ugo, Y. Lecluse, A. Bennaceur-Griscelli, and W. Vainchenker Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells Blood, September 1, 2006; 108(5): 1551 - 1554. [Abstract] [Full Text] [PDF]

				R. Yagi, D. McBurney, and W. E. Horton Jr. Bcl-2 Positively Regulates Sox9-dependent Chondrocyte Gene Expression by Suppressing the MEK-ERK1/2 Signaling Pathway J. Biol. Chem., August 26, 2005; 280(34): 30517 - 30525. [Abstract] [Full Text] [PDF]

				T. Kamata, J. Kang, T.-H. Lee, L. Wojnowski, C. A. Pritchard, and A. D. Leavitt A critical function for B-Raf at multiple stages of myelopoiesis Blood, August 1, 2005; 106(3): 833 - 840. [Abstract] [Full Text] [PDF]

				E. Karl, K. Warner, B. Zeitlin, T. Kaneko, L. Wurtzel, T. Jin, J. Chang, S. Wang, C.-Y. Wang, R. M. Strieter, et al. Bcl-2 Acts in a Proangiogenic Signaling Pathway through Nuclear Factor-{kappa}B and CXC Chemokines Cancer Res., June 15, 2005; 65(12): 5063 - 5069. [Abstract] [Full Text] [PDF]

				S. Plenchette, S. Cathelin, C. Rebe, S. Launay, S. Ladoire, O. Sordet, T. Ponnelle, N. Debili, T.-H. Phan, R.-A. Padua, et al. Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal-mediated event Blood, October 1, 2004; 104(7): 2035 - 2043. [Abstract] [Full Text] [PDF]