title: Basal p38 mitogen-activated protein kinase regulates unliganded glucocorticoid receptor function in airway smooth muscle cells.
abstract: Like many steroid receptors, the glucocorticoid (GC) receptor (GR) is a phosphoprotein. Although there are multiple phosphorylation sites critical for GR transcriptional activity (i.e., serine [S]203, S211, and S226), their respective role in driving GR functions is highly cell specific. We have recently identified protein phosphatase 5 as an essential Ser/Thr phosphatase responsible for impairing GR function via S211 dephosphorylation in airway smooth muscle (ASM) cells. Because p38 mitogen-activated protein kinase (MAPK) directly phosphorylates GR in different cell types in a stimulus- and cell-dependent manner, we investigated the role of p38 MAPK on GR phosphorylation and function in ASM cells. Cells were transfected with 100 nM p38 MAPK small interfering RNA or 2 μg MAPK kinase 3 expression vector (a specific kinase that directly activates p38 MAPK) in the presence or absence of fluticasone (100 nM) and/or p38 MAPK pharmacological inhibitor SB203580. We found that p38 MAPK blockade positively regulates GR nuclear translocation and GR-dependent induction of the steroid-target gene GC-induced leucine zipper in a hormone-independent manner. We also found that p38 MAPK-dependent regulation of GR functions was associated with a differential action on GR phosphorylation at S203 and S211 residues. This study demonstrated that the inactive state of GR in resting conditions is not only ensured by the absence of the GC ligand but also by p38 MAPK-dependent phosphorylation of unliganded GR at specific residues, which appears to be important in determining the overall GC responsiveness of ASM cells.
authors.affiliation: 1 Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, Pennsylvania; and.
authors.forename: Belaid
authors.initials: B
authors.lastname: Bouazza
authors.forename: Manel
authors.initials: M
authors.lastname: Debba-Pavard
authors.forename: Yassine
authors.initials: Y
authors.lastname: Amrani
authors.forename: Lauren
authors.initials: L
authors.lastname: Isaacs
authors.forename: Danielle
authors.initials: D
authors.lastname: O'Connell
authors.forename: Sara
authors.initials: S
authors.lastname: Ahamed
authors.forename: Danielle
authors.initials: D
authors.lastname: Formella
authors.forename: Omar
authors.initials: O
authors.lastname: Tliba
mesh_terms: D002478:Cells, Cultured; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016350:Leucine Zippers / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D007093:Imidazoles; D011725:Pyridines; D011965:Receptors, Glucocorticoid; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
references.citation: Cell. 1988 Dec 2;55(5):899-906
references.pmid: 3191531
references.citation: PLoS One. 2012;7(7):e41582
references.pmid: 22911818
references.citation: Exp Hematol. 2006 Nov;34(11):1542-52
references.pmid: 17046574
references.citation: Arthritis Rheum. 2009 Feb;60(2):335-44
references.pmid: 19180516
references.citation: Curr Opin Pharmacol. 2004 Aug;4(4):372-7
references.pmid: 15251131
references.citation: Thorax. 2008 Sep;63(9):784-90
references.pmid: 18492738
references.citation: J Clin Invest. 2003 May;111(10):1475-86
references.pmid: 12750397
references.citation: Arch Biochem Biophys. 2008 Jul 1;475(1):1-6
references.pmid: 18424253
references.citation: Mol Endocrinol. 2005 Jun;19(6):1569-83
references.pmid: 15817653
references.citation: Mol Endocrinol. 1994 Feb;8(2):189-96
references.pmid: 8170475
references.citation: J Biol Chem. 2005 Mar 25;280(12):11120-6
references.pmid: 15657031
references.citation: Mol Endocrinol. 2006 May;20(5):971-83
references.pmid: 16410316
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):317-24
references.pmid: 19217767
references.citation: Mol Med. 2012 May 09;18:433-44
references.pmid: 22231731
references.citation: Biologics. 2008 Dec;2(4):845-54
references.pmid: 19707462
references.citation: J Biol Chem. 2003 Jul 4;278(27):24624-8
references.pmid: 12730213
references.citation: Eur Respir J. 2010 Apr;35(4):750-6
references.pmid: 19840967
references.citation: J Biol Chem. 1997 Apr 4;272(14):9287-93
references.pmid: 9083064
references.citation: Mol Endocrinol. 2007 Mar;21(3):625-34
references.pmid: 17185395
references.citation: Mol Endocrinol. 2010 Sep;24(9):1748-64
references.pmid: 20660302
references.citation: Chest. 2011 Jun;139(6):1470-1479
references.pmid: 21652557
references.citation: Mol Pharmacol. 2011 Dec;80(6):1128-35
references.pmid: 21917909
references.citation: Eur J Pharmacol. 2006 Mar 8;533(1-3):118-32
references.pmid: 16469308
references.citation: Am J Respir Cell Mol Biol. 2012 Oct;47(4):464-73
references.pmid: 22592921
references.citation: Ann N Y Acad Sci. 2004 Jun;1024:86-101
references.pmid: 15265775
references.citation: Gastroenterology. 2002 Jan;122(1):7-14
references.pmid: 11781274
references.citation: PLoS One. 2011;6(12):e27627
references.pmid: 22205926
references.citation: J Biol Chem. 2011 Jun 3;286(22):19297-310
references.pmid: 21474440
references.citation: FASEB J. 2002 Nov;16(13):1832-4
references.pmid: 12223450
references.citation: J Biol Chem. 2004 Mar 19;279(12):11957-66
references.pmid: 14704147
references.citation: Leuk Res. 2009 May;33(5):717-27
references.pmid: 19012965
references.citation: J Biol Chem. 1995 Jul 21;270(29):17535-40
references.pmid: 7615559
references.citation: Am J Respir Cell Mol Biol. 2008 Apr;38(4):463-72
references.pmid: 17947510
references.citation: J Allergy Clin Immunol. 2012 Oct;130(4):877-85.e5
references.pmid: 22947346
references.citation: Am J Physiol. 1989 Feb;256(2 Pt 1):C329-35
references.pmid: 2645779
references.citation: Nature. 1987 Jan 22-28;325(6102):365-8
references.pmid: 3808033
references.citation: Mol Endocrinol. 2007 Jul;21(7):1552-68
references.pmid: 17440046
references.citation: Mol Endocrinol. 2002 Oct;16(10):2382-92
references.pmid: 12351702
references.citation: Mol Endocrinol. 2008 Aug;22(8):1754-66
references.pmid: 18483179
references.citation: Am J Physiol Endocrinol Metab. 2010 Aug;299(2):E299-307
references.pmid: 20516260
references.citation: Mol Endocrinol. 2009 Nov;23(11):1726-45
references.pmid: 19812390
references.citation: J Biol Chem. 2002 Jul 19;277(29):26573-80
references.pmid: 12000743
references.citation: Mol Psychiatry. 2004 Jan;9(1):65-75
references.pmid: 14699442
references.citation: Mol Endocrinol. 2007 Oct;21(10):2311-9
references.pmid: 17536004
references.citation: J Allergy Clin Immunol. 2002 Apr;109(4):649-57
references.pmid: 11941315
references.citation: J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):11-21
references.pmid: 17070034
references.citation: J Steroid Biochem Mol Biol. 2003 Feb;84(2-3):171-80
references.pmid: 12711001
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2050-5
references.pmid: 9482836
references.citation: Nat Rev Drug Discov. 2003 Sep;2(9):717-26
references.pmid: 12951578
references.citation: Mol Endocrinol. 2006 Mar;20(3):560-72
references.pmid: 16239257