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Originally published In Press as doi:10.1074/jbc.M205085200 on August 22, 2002

J. Biol. Chem., Vol. 277, Issue 44, 42188-42196, November 1, 2002
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Inhibition of Glucocorticoid-induced Apoptosis in 697 Pre-B Lymphocytes by the Mineralocorticoid Receptor N-terminal Domain*

Sonia L. PlaneyDagger , Assia Derfoul§, Andrzej Steplewski, Noreen M. Robertson, and Gerald Litwack

From the Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The glucocorticoid and mineralocorticoid receptors (GR and MR) share considerable structural and functional homology and bind as homodimers to hormone-response elements. We have shown previously that MR and GR can form heterodimers that inhibit transcription from a glucocorticoid (GC)-responsive gene and that this inhibition was mediated by the N-terminal domain (NTD) of MR. In this report, we examined the effect of NTD-MR on GC-induced apoptosis in the GC-sensitive pre-B lymphoma cell line, 697. In GC-treated 697 cells, we demonstrated that stable expression of NTD-MR blocks apoptosis and inhibits proteolytic processing of pro-caspases-3, -8, and -9 and poly(ADP-ribose) polymerase. Importantly, gel shift and immunoprecipitation analyses revealed a direct association between the GR and amino acids 203-603 of NTD-MR. We observed down-regulation of c-Myc and of the anti-apoptotic proteins Bcl-2 and Bfl-1 as well as high levels of the pro-apoptotic proteins Bax and Bid. Conversely, cells stably expressing NTD-MR exhibited increased expression of Bcl-2 and Bfl-1 and diminished levels of Bid and Bax. These data provide a potential mechanism for the observed inhibition of cytochrome c and Smac release from the mitochondria of NTD-MR cells and resultant resistance to GC-induced apoptosis. Thus, NTD-MR may mediate GC effects through heterodimerization with GR and ensuing inhibition of GC-regulated gene transcription.

* This work was supported in part by National Institutes of Health Grant AI/HL 40976 (to G. L.) and American Lung Association Grant RG-034N (to N. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Supported by National Institutes of Health Training Grant 5T32 DK07705.

§ Present address: NIAMS, National Institutes of Health, Rm. 3W17, 13 South Dr., MSC5755, Bethesda, MD 20892.

To whom correspondence should be addressed: Thomas Jefferson University, 233 S. 10th St., BLSB 350, Philadelphia, PA 19107. Tel.: 215-503-4634; Fax: 215-503-5393; E-mail: Gerry.Litwack@mail.tju.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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