RGS13 acts as a nuclear repressor of CREB.
Cyclic AMP-induced phosphorylation of the transcription factor CREB elicits expression of genes mediating diverse biological functions. In lymphoid organs, the neurotransmitter norepinephrine stimulates beta(2)-adrenergic receptors on B lymphocytes to promote CREB-dependent expression of genes like the B cell Oct 2 coactivator (OCA-B). Although CREB phosphorylation recruits cofactors such as CBP/p300 to stimulate transcription, bona fide endogenous inhibitors of CREB-coactivator or CREB-DNA interactions have not emerged. Here, we identified RGS13, a member of the Regulator of G protein Signaling (RGS) protein family, as a nuclear factor that suppresses CREB-mediated gene expression. cAMP or Ca(2+) signaling promoted RGS13 accumulation in the nucleus, where it formed a complex with phosphorylated CREB and CBP/p300. RGS13 reduced the apparent affinity of pCREB for both the CRE and CBP. B lymphocytes from Rgs13(-/-) mice had more beta(2)-agonist-induced OCA-B expression. Thus, RGS13 inhibits CREB-dependent transcription of target genes through disruption of complexes formed at the promoter.
Xie
Zhihui
Z
Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Geiger
Timothy R
TR
Johnson
Eric N
EN
Nyborg
Jennifer K
JK
Druey
Kirk M
KM
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D009687:Nuclear Proteins; D020710:RGS Proteins; C456322:RGS13 protein, human; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D050882:CREB-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs
Mol Cell Biol. 1997 Sep;17(9):5156-64
9271393
Mol Cell Biol. 1999 Dec;19(12):8123-35
10567538
J Biol Chem. 1999 Jul 9;274(28):19639-43
10391901
Trends Cell Biol. 2005 Sep;15(9):457-9
16084096
J Biol Chem. 2002 May 10;277(19):16768-74
11875076
J Biol Chem. 1999 Nov 26;274(48):34483-92
10567430
Trends Immunol. 2005 Apr;26(4):180-5
15797507
Protein Expr Purif. 2007 Oct;55(2):406-18
17703949
Nat Immunol. 2008 Jan;9(1):73-80
18026105
J Biol Chem. 2007 Nov 9;282(45):33064-75
17848575
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4481-6
9539763
FEBS Lett. 2004 Jan 16;557(1-3):93-8
14741347
Mol Endocrinol. 2004 Apr;18(4):791-806
14726488
J Biol Chem. 2002 Dec 13;277(50):48359-65
12374787
Nat Rev Mol Cell Biol. 2001 Aug;2(8):599-609
11483993
J Biol Chem. 2001 Apr 13;276(15):11719-28
11134034
Trends Biochem Sci. 1999 Jun;24(6):232-6
10366852
Mol Cell Biol. 2008 Feb;28(4):1383-92
18070920
Mol Cell Biol. 1996 Feb;16(2):694-703
8552098
EMBO J. 1998 Sep 1;17(17):5066-75
9724642
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4459-64
15753290
Pharmacol Ther. 2007 Dec;116(3):473-95
18006065
Semin Cell Dev Biol. 2006 Jun;17(3):363-76
16687250
J Biol Chem. 1998 Oct 30;273(44):28831-6
9786883
Science. 2003 Oct 31;302(5646):890-3
14593184
J Biol Chem. 2000 Mar 24;275(12):8263-6
10722651
J Biol Chem. 2007 Mar 30;282(13):9482-9491
17277356
PLoS Comput Biol. 2008 Apr 11;4(4):e1000060
18404207
J Biol Chem. 2002 Mar 15;277(11):9054-61
11782467
Mol Cell. 2003 Apr;11(4):1101-8
12718894
Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17622-7
15585582
Annu Rev Biochem. 1999;68:821-61
10872467
Mol Cell Endocrinol. 1994 May;101(1-2):R25-30
9397971
Mol Cell Biol. 2001 Apr;21(7):2249-58
11259575
J Immunol. 2002 Sep 1;169(5):2507-15
12193720
Front Biosci. 2004 Jan 01;9:100-3
14766349
Mol Cell. 1998 Sep;2(3):353-9
9774973
Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13572-7
15342915
J Biol Chem. 2004 May 28;279(22):23394-404
15024018
J Biol Chem. 2007 Jul 6;282(27):19872-83
17491014
J Biol Chem. 2002 Nov 1;277(44):42241-8
12196545
Cell Signal. 2004 Nov;16(11):1211-27
15337521
Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7216-20
9207071
Mol Biol Cell. 2000 Sep;11(9):3155-68
10982407
Diabetologia. 2004 May;47(5):926-36
15085339
Cell. 1997 Dec 12;91(6):741-52
9413984