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