title: Opposing roles of FoxP1 and Nfat3 in transcriptional control of cardiomyocyte hypertrophy.
abstract: Cardiac homeostasis is maintained by a balance of growth-promoting and growth-modulating factors. Sustained elevation of calcium signaling can induce cardiac hypertrophy through activation of Nfat family transcription factors. FoxP family transcription factors are known to interact with Nfat proteins and to modulate their transcriptional activities in lymphocytes. We investigated FoxP1 interaction with Nfat3 (Nfatc4) and their effects on transcription of hypertrophy-associated genes in neonatal rat cardiomyocytes. FoxP1-Nfat3 complexes were visualized using bimolecular fluorescence complementation (BiFC) analysis. Calcineurin activation induced FoxP1-Nfat3 BiFC complex formation. Amino acid substitutions in the predicted interaction interface inhibited it. FoxP1 repressed hypertrophy-associated genes (Myh7, Rcan1, Cx43, Anf, and Bnp) and counteracted their activation by constitutively nuclear Nfat3 (cnNfat3). In contrast, FoxP1 activated genes that maintain normal heart functions (Myh6 and p57Kip2) and cnNfat3 counteracted their activation by FoxP1. Amino acid substitutions in FoxP1 or cnNfat3 that inhibited their interaction abrogated the activation of hypertrophy-associated gene transcription by cnNfat3 and the repression of these genes by FoxP1. FoxP1 and Nfat3 co-occupied the promoter regions of hypertrophy-associated genes in neonatal and adult heart tissue. FoxP1 counteracted hypertrophic cardiomyocyte growth, and connexin 43 mislocalization caused by cnNfat3 expression. These data suggest that the opposing transcriptional activities of FoxP1 and Nfat3 maintain cardiomyocyte homeostasis.
authors: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109-0650, USA.
authors: Shoumei
authors: S
authors: Bai
authors: Tom K
authors: TK
authors: Kerppola
references: Chin Med J (Engl). 2001 Feb;114(2):183-5
references: 11780203
references: Circ Res. 1987 Jul;61(1):70-6
references: 3608112
references: Structure. 2006 Jan;14(1):159-66
references: 16407075
references: Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
references: 16936699
references: Circ Res. 2000 Mar 3;86(4):386-90
references: 10700442
references: Genes Dev. 2010 Aug 15;24(16):1746-57
references: 20713518
references: Cell. 1998 Apr 17;93(2):215-28
references: 9568714
references: Mol Cell. 2002 Apr;9(4):789-98
references: 11983170
references: Am J Physiol. 1994 Jul;267(1 Pt 2):H400-5
references: 8048605
references: Nat Struct Biol. 2003 Oct;10(10):800-6
references: 12949493
references: J Card Fail. 2007 May;13(4):318-29
references: 17517353
references: Cell. 2006 Jul 28;126(2):375-87
references: 16873067
references: J Am Coll Cardiol. 1998 Sep;32(3):800-7
references: 9741530
references: Arch Biochem Biophys. 2008 Feb 1;470(1):93-102
references: 18061571
references: Nat Immunol. 2006 Aug;7(8):819-26
references: 16819554
references: Am J Physiol Cell Physiol. 2001 May;280(5):C1262-76
references: 11287340
references: J Clin Invest. 1990 Dec;86(6):1913-20
references: 2174912
references: J Biol Chem. 2009 Oct 9;284(41):28319-28331
references: 19696026
references: Circ Res. 2004 Feb 20;94(3):e18-26
references: 14739160
references: Genes Dev. 2008 Mar 15;22(6):740-5
references: 18347093
references: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7915-20
references: 9653115
references: J Am Coll Cardiol. 2004 Dec 21;44(12):2390-7
references: 15607403
references: Nature. 1998 Mar 12;392(6672):182-6
references: 9515963
references: J Cardiovasc Pharmacol. 1998;31 Suppl 1:S302-5
references: 9595465
references: Cell. 2001 Jun 29;105(7):863-75
references: 11439183
references: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3328-33
references: 11248078
references: Circ Res. 2008 Jan 4;102(1):16-31
references: 18174472
references: Cardiovasc Res. 2008 Oct 1;80(1):9-19
references: 18519446
references: Science. 2004 Sep 10;305(5690):1619-22
references: 15361625
references: BMC Physiol. 2008 Feb 29;8:4
references: 18312674
references: Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):7000-5
references: 20351294
references: Nat Genet. 2001 Jan;27(1):18-20
references: 11137992
references: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):669-74
references: 12515860
references: Circulation. 2006 Sep 19;114(12):1269-76
references: 16952980
references: Cardiovasc Res. 2003 Aug 1;59(2):380-9
references: 12909321
references: Curr Opin Immunol. 2007 Jun;19(3):287-93
references: 17433870
references: Circulation. 2005 May 10;111(18):2339-46
references: 15867177
references: Development. 2004 Sep;131(18):4477-87
references: 15342473
references: J Biol Chem. 2003 Jul 4;278(27):24259-68
references: 12692134
references: Am J Hypertens. 1992 May;5(5 Pt 1):276-80
references: 1533768
references: Circ Res. 2008 Mar 28;102(6):686-94
references: 18218983
references: Circ Res. 2003 Jun 27;92(12):1305-13
references: 12750314
references: Circ Res. 2000 Dec 8;87(12):E61-8
references: 11110780
references: J Biol Chem. 2005 May 27;280(21):20814-23
references: 15781459
references: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5138-43
references: 15790681
references: Science. 1993 Oct 29;262(5134):750-4
references: 8235597
references: Nature. 1998 Mar 12;392(6672):186-90
references: 9515964
references: Circulation. 2006 Sep 12;114(11):1159-68
references: 16952979
references: Mol Med. 2002 Nov;8(11):750-60
references: 12520092
references: J Clin Invest. 2010 Jan;120(1):266-79
references: 20038810
references: Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H533-9
references: 12124198
references: Mol Cell Biol. 2003 Mar;23(5):1737-49
references: 12588992
references: J Mol Cell Cardiol. 2000 Apr;32(4):697-709
references: 10756124
references: Int J Biochem Cell Biol. 2008;40(10):2023-39
references: 18407781
references: Nature. 1998 Mar 5;392(6671):42-8
references: 9510247