Homodimerization of the Glucocorticoid Receptor Is Not Essential for Response Element Binding: Activation of the PhenylethanolamineN-Methyltransferase Gene by Dimerization-Defective Mutants
Year: 2003
Type: article
Abstract: We have tested the commonly held hypothesis that glucocorticoid receptors (GRs) must dimerize via their DNA binding domain (DBD) to bind to glucocorticoid response elements (GRE) and induce gene expression. Guided by the GR dimerization-deficient dim/dim knock-in mouse, which expresses normal mRNA levels of the strictly GR-dependent phenylethanolamine N-methyltransferase (PNMT) gene, we analyzed in detail the regulation of the PNMT 5'-flanking region using wild-type GR (GRwt) and GR dimer mutants (GRdms). We demonstrated that mouse and rat PNMT 5'-regulatory fragments are more strongly induced by GRdms than by GRwt. Footprinting analysis revealed five regions where a GR-DBD peptide could bind. We delineated a 105-bp region containing two footprints with near-consensus glucocorticoid response elements and multiple half-sites that was sufficient for transactivation via both GRwt and GRdms. Finally, we demonstrated direct binding of GRdms proteins to this responsive region using EMSA. We propose that on a subset of GR-responsive promoters, exemplified by the PNMT gene, GRs can form concerted multimers in a manner that is independent of the DBD-dimer interface. We further suggest that protein-DNA and protein-protein interactions that support such complexes are essential for activation of this type of gene, and that DNA binding of GR might be essential to survival.
Source: Molecular Endocrinology
DOI: 10.1210/me.2002-0305
Authors: Melanie Adams, Onno C. Meijer, Jian Wang, Aditi Bhargava, David Pearce
Institution: University of California, San Francisco
Language: English
Subfield: Endocrinology
Domain: Life Sciences
Open Access status: bronze
Award: G4696470309
OpenAlex ID: W2027749435