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J. Biol. Chem., Vol. 283, Issue 16, 10698-10706, April 18, 2008

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Constitutive Production of NF-B2 p52 Is Not Tumorigenic but Predisposes Mice to Inflammatory Autoimmune Disease by Repressing Bim Expression^*

From the Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo Health Science Campus, Toledo, Ohio 43614

Normal development of the immune system requires regulated processing of NF-B2 p100 to p52, which activates NF-B2 signaling. Constitutive production of p52 has been suggested as a major mechanism underlying lymphomagenesis induced by NF-B2 mutations, which occur recurrently in a variety of human lymphoid malignancies. To test the hypothesis, we generated transgenic mice with targeted expression of p52 in lymphocytes. In contrast to their counterparts expressing the tumor-derived NF-B2 mutant p80HT, which develop predominantly B cell tumors, p52 transgenic mice are not prone to lymphomagenesis. However, they are predisposed to inflammatory autoimmune disease characterized by multiorgan infiltration of activated lymphocytes, high levels of autoantibodies in the serum, and immune complex glomerulonephritis. p52, but not p80HT, represses Bim expression, leading to defects in apoptotic processes critical for elimination of autoreactive lymphocytes and control of immune response. These findings reveal distinct signaling pathways for actions of NF-B2 mutants and p52 and suggest a causal role for sustained NF-B2 activation in the pathogenesis of autoimmunity.

Received for publication, January 30, 2008

^* This work was supported by American Cancer Society Grant RSG-03-173-01-CCG and National Cancer Institute Grant R01 CA106550 (to H.-F. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ These authors contributed equally to this work.

² Present address: The CBR Institute for Biomedical Research, Warren Alpert Bldg., 200 Longwood Ave., Boston, MA 02115.

³ To whom correspondence should be addressed: Dept. of Biochemistry and Cancer Biology, College of Medicine, University of Toledo Health Science Campus, BHSB 461, 3035 Arlington Ave., Toledo, OH 43614. Tel.: 419-383-6653; Fax: 419-383-6228; E-mail: han-fei.ding{at}utoledo.edu.

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