Specifying Cell Fate with Bcl-2 Family Members

Abstract

The Bcl-2 family of proteins is best known for their roles in programmed cell death and consists of antiapoptotic members (Bcl-2 and Bcl-X L , for example) and proapoptotic members (Bax and Bak, for example). Haughn et al. provide evidence that Bcl-2 and Bcl-X L also specify cell fate in hematopoietic cell differentiation. When the multipotent hematopoietic cells (FDCP-Mix) cells were deprived of interleukin 3 (IL-3), overexpression of Bcl-2 resulted in myeloid cells (granulocytes, macrophages, and monocytes); whereas overexpression of Bcl-X L resulted in erythroid cells. By replacing the Bcl-2 homology 4 domain (BH4) of Bcl-2 with that of Bcl-X L , IL-3 withdrawal led to the production of erythroid cells, just like those seen with Bcl-X L overexpression. Thus, the BH4 domain is essential for the difference in cell fate. Immunoblots showed that only overexpression of Bcl-2 decreased Raf-1, a kinase in the mitogen-activated protein kinase cascade, without decreasing the mRNA for Raf-1 and without affecting the expression of other Raf isoforms. Coexpression of Raf-1, either the wild type or a kinase-inactive truncated version, along with Bcl-2 resulted in erythroid cells in response to IL-3 withdrawal. Geldamycin, an inhibitor of the chaperone heat shock protein 90, decreased Raf-1 levels in Bcl-X L , which resulted in the production of myeloid cells. Thus, the authors propose that Bcl-2 influences Raf-1 stability, which serves as a switch for differentiation. Normal levels of Raf-1 are associated with an erythroid cell fate, whereas loss of Raf-1 (in the presence of overexpressed Bcl-2) is associated with myeloid cell fates. These data support the expansion of roles for Bcl-2 proteins beyond cell survival into cell fate specification. L. Haughn, R. G. Hawley, D. K. Morrison, H. von Boehmer, D. M. Hockenbery, BCL-2 and BCL-X L restrict lineage choice during hematopoietic differentiations. J. Biol. Chem. 278 , 25158-25165 (2003). [Abstract] [Full Text]