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Inhibition of glucocorticoid-induced apoptosis in 697 pre-B lymphocytes by the mineralocorticoid receptor N-terminal domain
Journal article   Open access   Peer reviewed

Inhibition of glucocorticoid-induced apoptosis in 697 pre-B lymphocytes by the mineralocorticoid receptor N-terminal domain

Sonia L Planey, Assia Derfoul, Andrzej Steplewski, Noreen M Robertson and Gerald Litwack
The Journal of biological chemistry, v 277(44), pp 42188-42196
01 Nov 2002
DOI: https://doi.org/10.1074/jbc.M205085200
PMID: 12194973
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1074/jbc.M205085200View
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Abstract

Active Transport, Cell Nucleus Apoptosis - drug effects Apoptosis Regulatory Proteins Carrier Proteins - metabolism Caspases - metabolism Cytochrome c Group - metabolism Dimerization Glucocorticoids - antagonists & inhibitors Humans Intracellular Signaling Peptides and Proteins Minor Histocompatibility Antigens Mitochondrial Proteins - metabolism Peptide Fragments - physiology Poly(ADP-ribose) Polymerases - metabolism Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology Proto-Oncogene Proteins c-bcl-2 - analysis Receptors, Mineralocorticoid - physiology Transcription, Genetic Tumor Cells, Cultured
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.

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Biochemistry & Molecular Biology
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