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J. Biol. Chem., Vol. 281, Issue 52, 39806-39818, December 29, 2006

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The Role of MAPKs in B Cell Receptor-induced Down-regulation of Egr-1 in Immature B Lymphoma Cells^*

Jiyuan Ke, Murali Gururajan^¶, Anupam Kumar, Alan Simmons, Lilia Turcios, Ralph L. Chelvarajan, David M. Cohen^||, David L. Wiest^**, John G. Monroe, and Subbarao Bondada^¶1

From the Department of Microbiology, Immunology, and Molecular Genetics, the Sanders-Brown Center on Aging, the ^¶Graduate Center for Toxicology, and the Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, the ^||Department of Medicine, Oregon Health & Science University, Portland, Oregon 97239, ^**the Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, and the Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Cross-linking of the B cell receptor (BCR) on the immature B lymphoma cell line BKS-2 induces growth inhibition and apoptosis accompanied by rapid down-regulation of the immediate-early gene egr-1. In these lymphoma cells, egr-1 is expressed constitutively and has a prosurvival role, as Egr-1-specific antisense oligonucleotides or expression of a dominant-negative inhibitor of Egr-1 also prevented the growth of BKS-2 cells. Moreover, enhancement of Egr-1 protein with phorbol 12-myristate 13-acetate or an egr-1 expression vector rescued BKS-2 cells from BCR signal-induced growth inhibition. Nuclear run-on and mRNA stability assays indicated that BCR-derived signals act at the transcriptional level to reduce egr-1 expression. Inhibitors of ERK and JNK (but not of p38 MAPK) reduced egr-1 expression at the protein level. Transcriptional regulation appears to have a role because egr-1 promoter-driven luciferase expression was reduced by ERK and JNK inhibitors. Promoter truncation experiments suggested that several serum response elements are required for MAPK-mediated egr-1 expression. Our study suggests that BCR signals reduce egr-1 expression by inhibiting activation of ERK and JNK. Unlike ERK and JNK, p38 MAPK reduces constitutive expression of egr-1. Unlike the immature B lymphoma cells, normal immature B cells did not exhibit constitutive MAPK activation. BCR-induced MAPK activation was modest and transient with a small increase in egr-1 expression in normal immature B cells consistent with their inability to proliferate in response to BCR cross-linking.

Received for publication, May 16, 2006 , and in revised form, October 23, 2006.

^* This work was supported by National Institutes of Health Grant 5P01CA092372 (to S. B.). 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.

¹ To whom correspondence should be addressed: Sanders-Brown Center on Aging, Rm. 329A, University of Kentucky, Lexington, KY 40536-0230. Tel.: 859-323-8102 (ext. 266); Fax: 859-323-2866; E-mail: bondada{at}uky.edu.

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