Homodimerization of the Glucocorticoid Receptor Is Not Essential for Response Element Binding: Activation of the Phenylethanolamine N-Methyltransferase Gene by Dimerization-Defective Mutants
Open accessAbstract
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.
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The single point mutation A458T engineered in GRdim is unlikely to fully abrogate the formation of functional GR homodimers.
“The single point mutation A458T engineered in GRdim is thus unlikely to fully abrogate the formation of functional GR homodimers (30, 112, 113).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [112]
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- Authors
- Adams, M., Meijer, O. C., Wang, J., Bhargava, A., & Pearce, D.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Pearce, David
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2003-12
- Volume
- 17
- Issue
- 12
- Pages
- 2583-2592
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2027749435
- Cited by
- 113
- References
- 41
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 1 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 6 · 2013: 2 · 2012: 5
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, San Francisco
- National Institute of Diabetes and Digestive and Kidney Diseases (DK51151)
- Department of Medicine, University of California, San Francisco
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- glucocorticoid receptor, receptor homodimerization, DNA-binding domain, glucocorticoid response element, phenylethanolamine N-methyltransferase, gene expression regulation, promoter binding, protein-DNA interactions, protein-protein interaction, transcriptional activation, half-sites
- MeSH terms
- Animals, Base Sequence, Cell Line, Chlorocebus aethiops, Cloning, Molecular, Deoxyribonuclease I, Molecular Sequence Data, Phenylethanolamine N-Methyltransferase, Plasmids, Receptors, Glucocorticoid, Recombinant Proteins, Gene Expression Regulation, Enzymologic, Mutagenesis, Mutagenesis, Site-Directed, Sequence Deletion, Genes, Reporter, DNA Footprinting, Dimerization, Amino Acid Substitution, Mice, Rats
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