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J. Biol. Chem., Vol. 279, Issue 19, 19523-19530, May 7, 2004

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RasGRP1 Sensitizes an Immature B Cell Line to Antigen Receptor-induced Apoptosis^*

Benoit Guilbault and Robert J. Kay

From the Terry Fox Laboratory, British Columbia Cancer Agency, and the Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4E6, Canada

RasGRP1 is a guanine nucleotide exchange factor that activates Ras GTPases and is activated downstream of antigen receptors on both T and B lymphocytes. Ras-GRP1 provides signals to immature T cells that confer survival and proliferation, but RasGRP1 also promotes T cell receptor-mediated deletion of mature T cells. We used the WEHI-231 cell line as an experimental system to determine whether RasGRP1 can serve as a quantitative modifier of B cell receptor-induced deletion of immature B cells. A 2-fold elevation in RasGRP1 expression markedly increased apoptosis of WEHI-231 cells following B cell receptor ligation, whereas a dominant negative mutant of RasGRP1 suppressed B cell receptor-induced apoptosis. Activation of ERK1 or ERK2 kinases was not required for RasGRP1-mediated apoptosis. Instead, elevated RasGRP1 expression caused down-regulation of NF-B and Bcl-x_L, which provide survival signals counter-acting apoptosis induction by B cell receptor. Inhibition of NF-B was sufficient to enhance B cell receptor-induced apoptosis of WEHI-231 cells, and ligation of co-stimulatory receptors that activate NF-B suppressed the ability of RasGRP1 to promote B cell receptor-induced apoptosis. These experiments define a novel apoptosis-promoting pathway leading from B cell receptor to the inhibition of NF-B and demonstrate that differential expression of RasGRP1 has the potential to modulate the sensitivities of B cells to negative selection following antigen encounter.

Received for publication, December 29, 2003 , and in revised form, February 12, 2004.

^* This work was supported by a grant from the Canadian Institutes for Health Research (to R. J. K.). 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.

Recipient of a Studentship from the Natural Sciences and Engineering Research Council of Canada.

To whom correspondence should be addressed: Terry Fox Laboratory, British Columbia Cancer Agency, 600 West 10th Ave., Vancouver, BC V5Z 4E6, Canada. Tel.: 604-877-6070; Fax: 604-877-0712; E-mail: rkay{at}bccrc.ca.

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				N. Beaulieu, B. Zahedi, R. E. Goulding, G. Tazmini, K. V. Anthony, S. L. Omeis, D. R. de Jong, and R. J. Kay Regulation of RasGRP1 by B Cell Antigen Receptor Requires Cooperativity between Three Domains Controlling Translocation to the Plasma Membrane Mol. Biol. Cell, August 1, 2007; 18(8): 3156 - 3168. [Abstract] [Full Text] [PDF]