Molecular Endocrinology, Vol 6, 1451-1457, Copyright © 1992 by Endocrine Society

ARTICLES

Modulation of glucocorticoid receptor function by protein kinase A

PN Rangarajan, K Umesono and RM Evans
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037.

Protein kinase A (PKA) has been shown to modulate the pattern of gene expression via transcription factors such as cAMP response element binding protein. However, in F9 embryonal carcinoma cells which lack endogenous functional cAMP response element binding protein, we have found that PKA is still able to control gene transcription through the glucocorticoid receptor (GR) by up-regulating its hormone-dependent trans-activation. Dose-response analysis indicates that PKA does not alter the ligand binding affinity of GR. PKA seems to act through the DNA binding domain of GR, since GR mutants which lack either the amino- terminal or the ligand binding domain are still able to be up-regulated by PKA. In support of this proposal, we demonstrate that PKA can enhance the DNA binding activity of GR. Our results suggest a novel mechanism by which PKA modulates the steroid sensitivity of a target cell by enhancing the DNA binding activity of GR for its cognate hormone response elements.

This article has been cited by other articles:

				M. Kaur, J. E. Chivers, M. A. Giembycz, and R. Newton Long-Acting 2-Adrenoceptor Agonists Synergistically Enhance Glucocorticoid-Dependent Transcription in Human Airway Epithelial and Smooth Muscle Cells Mol. Pharmacol., January 1, 2008; 73(1): 203 - 214. [Abstract] [Full Text] [PDF]

				C. M. Pariante The glucocorticoid receptor: part of the solution or part of the problem? J Psychopharmacol, July 1, 2006; 20(4 Suppl): 79 - 84. [Abstract] [PDF]

				M. O. Leonard, C. Godson, H. R. Brady, and C. T. Taylor Potentiation of Glucocorticoid Activity in Hypoxia through Induction of the Glucocorticoid Receptor J. Immunol., February 15, 2005; 174(4): 2250 - 2257. [Abstract] [Full Text] [PDF]

				A Cote-Velez, L Perez-Martinez, M Y Diaz-Gallardo, C Perez-Monter, A Carreon-Rodriguez, J-L Charli, and P Joseph-Bravo Dexamethasone represses cAMP rapid upregulation of TRH gene transcription: identification of a composite glucocorticoid response element and a cAMP response element in TRH promoter J. Mol. Endocrinol., February 1, 2005; 34(1): 177 - 197. [Abstract] [Full Text] [PDF]

				C. L. Raison and A. H. Miller When Not Enough Is Too Much: The Role of Insufficient Glucocorticoid Signaling in the Pathophysiology of Stress-Related Disorders Am J Psychiatry, September 1, 2003; 160(9): 1554 - 1565. [Abstract] [Full Text] [PDF]

				K. De Bosscher, W. Vanden Berghe, and G. Haegeman The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression Endocr. Rev., August 1, 2003; 24(4): 488 - 522. [Abstract] [Full Text] [PDF]

				K. M. Coleman, M. Dutertre, A. El-Gharbawy, B. G. Rowan, N. L. Weigel, and C. L. Smith Mechanistic Differences in the Activation of Estrogen Receptor-alpha (ERalpha )- and ERbeta -dependent Gene Expression by cAMP Signaling Pathway(s) J. Biol. Chem., April 4, 2003; 278(15): 12834 - 12845. [Abstract] [Full Text] [PDF]

				F. Gay, P. Barath, C. Desbois-Le Peron, R. Metivier, R. Le Guevel, D. Birse, and G. Salbert Multiple Phosphorylation Events Control Chicken Ovalbumin Upstream Promoter Transcription Factor I Orphan Nuclear Receptor Activity Mol. Endocrinol., June 1, 2002; 16(6): 1332 - 1351. [Abstract] [Full Text] [PDF]

				R. Ogawa, M. B. Streiff, A. Bugayenko, and G. J. Kato Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21WAF1/CIP1 proteins in human acute lymphoblastic leukemia cells Blood, May 1, 2002; 99(9): 3390 - 3397. [Abstract] [Full Text] [PDF]

				W. Yang, S. J. Hyllner, and S. Christakos Interrelationship between signal transduction pathways and 1,25(OH)2D3 in UMR106 osteoblastic cells Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E162 - E170. [Abstract] [Full Text] [PDF]

				G. Lazennec, L. Canaple, D. Saugy, and W. Wahli Activation of Peroxisome Proliferator-Activated Receptors (PPARs) by Their Ligands and Protein Kinase A Activators Mol. Endocrinol., December 1, 2000; 14(12): 1962 - 1975. [Abstract] [Full Text]

				V. Doucas, Y. Shi, S. Miyamoto, A. West, I. Verma, and R. M. Evans Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor PNAS, October 4, 2000; (2000) 220413297. [Abstract] [Full Text]

				J. P. Northrop, D. Nguyen, S. Piplani, S. E. Olivan, S. T-S. Kwan, N. F. Go, C. P. Hart, and P. J. Schatz Selection of Estrogen Receptor {beta}- and Thyroid Hormone Receptor {beta}-Specific Coactivator-Mimetic Peptides Using Recombinant Peptide Libraries Mol. Endocrinol., May 1, 2000; 14(5): 605 - 622. [Abstract] [Full Text]

				C. M. Pariante, B. D. Pearce, T. L. Pisell, C. I. Sanchez, C. Po, C. Su, and A. H. Miller The Proinflammatory Cytokine, Interleukin-1{alpha}, Reduces Glucocorticoid Receptor Translocation and Function Endocrinology, September 1, 1999; 140(9): 4359 - 4366. [Abstract] [Full Text]

				Y. Makino, N. Yoshikawa, K. Okamoto, K. Hirota, J. Yodoi, I. Makino, and H. Tanaka Direct Association with Thioredoxin Allows Redox Regulation of Glucocorticoid Receptor Function J. Biol. Chem., January 29, 1999; 274(5): 3182 - 3188. [Abstract] [Full Text] [PDF]

				C. Massaad, N. Houard, M. Lombès, and R. Barouki Modulation of Human Mineralocorticoid Receptor Function by Protein Kinase A Mol. Endocrinol., January 1, 1999; 13(1): 57 - 65. [Abstract] [Full Text]

				V. M. Christoffels, T. Grange, K. H. Kaestner, T. J. Cole, G. J. Darlington, C. M. Croniger, and W. H. Lamers Glucocorticoid Receptor, C/EBP, HNF3, and Protein Kinase A Coordinately Activate the Glucocorticoid Response Unit of the Carbamoylphosphate Synthetase I Gene Mol. Cell. Biol., November 1, 1998; 18(11): 6305 - 6315. [Abstract] [Full Text]

				B. L. Wagner, J. D. Norris, T. A. Knotts, N. L. Weigel, and D. P. McDonnell The Nuclear Corepressors NCoR and SMRT Are Key Regulators of Both Ligand- and 8-Bromo-Cyclic AMP-Dependent Transcriptional Activity of the Human Progesterone Receptor Mol. Cell. Biol., March 1, 1998; 18(3): 1369 - 1378. [Abstract] [Full Text]

				C. M. Pariante, B. D. Pearce, T. L. Pisell, M. J. Owens, and A. H. Miller Steroid-Independent Translocation of the Glucocorticoid Receptor by the Antidepressant Desipramine Mol. Pharmacol., October 1, 1997; 52(4): 571 - 581. [Abstract] [Full Text]

				W. Bai, B. G. Rowan, V. E. Allgood, B. W. O'Malley, and N. L. Weigel Differential Phosphorylation of Chicken Progesterone Receptor in Hormone-dependent and Ligand-independent Activation J. Biol. Chem., April 18, 1997; 272(16): 10457 - 10463. [Abstract] [Full Text] [PDF]

				K. L. Crossin, M.-H. Tai, L. A. Krushel, V. P. Mauro, and G. M. Edelman Glucocorticoid receptor pathways are involved in the inhibition of astrocyte proliferation PNAS, March 18, 1997; 94(6): 2687 - 2692. [Abstract] [Full Text] [PDF]

				D. C. Leitman, C. H.R.M. Costa, H. Graf, J. D. Baxter, and R. C.J. Ribeiro Thyroid Hormone Activation of Transcription Is Potentiated by Activators of cAMP-dependent Protein Kinase J. Biol. Chem., September 6, 1996; 271(36): 21950 - 21955. [Abstract] [Full Text] [PDF]

				G. S. Takimoto, A. R. Hovland, D. M. Tasset, M. Y. Melville, L. Tung, and K. B. Horwitz Role of Phosphorylation on DNA Binding and Transcriptional Functions of Human Progesterone Receptors J. Biol. Chem., June 7, 1996; 271(23): 13308 - 13316. [Abstract] [Full Text] [PDF]

				B. S. Warren, P. Kusk, R. G. Wolford, and G. L. Hager Purification and Stabilization of Transcriptionally Active Glucocorticoid Receptor J. Biol. Chem., May 10, 1996; 271(19): 11434 - 11440. [Abstract] [Full Text] [PDF]

				H. Oshima, D. Szapary, and S. S. Simons Jr. The Factor Binding to the Glucocorticoid Modulatory Element of the Tyrosine Aminotransferase Gene Is a Novel and Ubiquitous Heteromeric Complex J. Biol. Chem., September 15, 1995; 270(37): 21893 - 21901. [Abstract] [Full Text] [PDF]

				V. M. Christoffels, P. E. M. H. Habets, A. T. Das, D. E. W. Clout, M. A. van Roon, A. F. M. Moorman, and W. H. Lamers A Single Regulatory Module of the Carbamoylphosphate Synthetase I Gene Executes Its Hepatic Program of Expression J. Biol. Chem., December 15, 2000; 275(51): 40020 - 40027. [Abstract] [Full Text] [PDF]

				V. Doucas, Y. Shi, S. Miyamoto, A. West, I. Verma, and R. M. Evans Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor PNAS, October 24, 2000; 97(22): 11893 - 11898. [Abstract] [Full Text] [PDF]