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Modulation of glucocorticoid receptor function by protein kinase A
P N Rangarajan1, K Umesono, R M Evans
1Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037.
Molecular Endocrinology (Baltimore, Md.)
|September 1, 1992
Summary
Protein kinase A (PKA) enhances gene transcription via the glucocorticoid receptor (GR) in F9 cells lacking CREB. PKA up-regulates GR
Area of Science:
- Molecular Biology
- Cellular Signaling
- Gene Regulation
Background:
- Protein kinase A (PKA) regulates gene expression through transcription factors like cAMP response element binding protein (CREB).
- F9 embryonal carcinoma cells lack functional CREB, presenting a unique model to study alternative PKA-mediated gene regulation.
- The glucocorticoid receptor (GR) is a key mediator of steroid hormone action and gene transcription.
Purpose of the Study:
- To investigate the mechanism by which PKA controls gene transcription in F9 cells lacking CREB.
- To determine if PKA can modulate the activity of the glucocorticoid receptor (GR).
- To elucidate the specific domain of GR involved in PKA-mediated regulation.
Main Methods:
- Dose-response analysis to assess PKA's effect on GR ligand binding affinity.
- Utilizing GR mutants lacking specific domains (amino-terminal, ligand-binding) to identify the PKA interaction site.
- Assessing the DNA binding activity of GR following PKA treatment.
Main Results:
- PKA up-regulates the hormone-dependent trans-activation of GR in F9 cells.
- PKA does not affect the ligand binding affinity of GR.
- PKA enhances GR's DNA binding activity, acting through the DNA binding domain, not the amino-terminal or ligand-binding domains.
Conclusions:
- PKA modulates steroid sensitivity in target cells through a novel mechanism.
- PKA enhances the DNA binding activity of GR to its cognate hormone response elements.
- This provides a new understanding of PKA's role in gene regulation beyond CREB.