title: Cardiac hypertrophy induced by active Raf depends on Yorkie-mediated transcription.
abstract: Organ hypertrophy can result from enlargement of individual cells or from cell proliferation or both. Activating mutations in the serine-threonine kinase Raf cause cardiac hypertrophy and contribute to Noonan syndrome in humans. Cardiac-specific expression of activated Raf also causes hypertrophy in Drosophila melanogaster. We found that Yorkie (Yki), a transcriptional coactivator in the Hippo pathway that regulates organ size, is required for Raf-induced cardiac hypertrophy in flies. Although aberrant activation of Yki orthologs stimulates cardiac hyperplasia in mice, cardiac-specific expression of an activated mutant form of Yki in fruit flies caused cardiac hypertrophy without hyperplasia. Knockdown of Yki caused cardiac dilation without loss of cardiomyocytes and prevented Raf-induced cardiac hypertrophy. In flies, Yki-induced cardiac hypertrophy required the TEA domain-containing transcription factor Scalloped, and, in mammalian cells, expression of mouse Raf(L613V), an activated form of Raf with a Noonan syndrome mutation, increased Yki-induced Scalloped activity. Furthermore, overexpression of Tgi (a Tondu domain-containing Scalloped-binding corepressor) in the fly heart abrogated Yki- or Raf-induced cardiac hypertrophy. Thus, crosstalk between Raf and Yki occurs in the heart and can influence Raf-mediated cardiac hypertrophy.
authors: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors: Lin
authors: L
authors: Yu
authors: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors: Joseph P
authors: JP
authors: Daniels
authors: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors: Huihui
authors: H
authors: Wu
authors: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. matthew.j.wolf@dm.duke.edu.
authors: Matthew J
authors: MJ
authors: Wolf
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000473:pathology*; D002352:Carrier Proteins; D049109:Cell Proliferation; D056970:Co-Repressor Proteins / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009929:Organ Size; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D019076:Transgenes; D000091102:YAP-Signaling Proteins
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D029721:Drosophila Proteins; D009687:Nuclear Proteins; C587951:Tgi protein, Drosophila; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases
references: Sci Signal. 2011 Oct 25;4(196 ):ra70
references: 22028467
references: Genes Dev. 2010 Oct 15;24(20):2294-302
references: 20952538
references: Cell Cycle. 2005 Mar;4(3):365-7
references: 15701972
references: Cell. 2014 Feb 27;156(5):893-906
references: 24581491
references: Cold Spring Harb Perspect Biol. 2012 Oct 01;4(10):null
references: 23028116
references: Oncogene. 2009 Apr 30;28(17):1916-27
references: 19330023
references: Development. 1993 Jun;118(2):401-15
references: 8223268
references: Dev Cell. 2013 Mar 11;24(5):459-71
references: 23484853
references: J Mol Cell Cardiol. 1986 Jan;18(1):39-53
references: 3950970
references: PLoS One. 2009 Sep 22;4(9):e7132
references: 19771157
references: Curr Biol. 2014 Sep 8;24(17):2012-7
references: 25127217
references: J Clin Invest. 2011 Mar;121(3):1009-25
references: 21339642
references: Mol Cell Biol. 1986 Aug;6(8):2839-46
references: 3491292
references: Dis Model Mech. 2013 Jul;6(4):964-76
references: 23580199
references: J Biol Chem. 2004 Jul 16;279(29):30800-6
references: 15140898
references: Cell. 2003 Aug 22;114(4):445-56
references: 12941273
references: Development. 2005 Dec;132(23):5283-93
references: 16284119
references: Science. 2011 Apr 22;332(6028):458-61
references: 21512031
references: Mech Dev. 2011 Mar-Apr;128(3-4):222-33
references: 21237266
references: J Vis Exp. 2009 Oct 13;(32):null
references: 19826399
references: Genes Dev. 2008 Jul 15;22(14):1962-71
references: 18579750
references: Dev Cell. 2008 Mar;14(3):377-87
references: 18258485
references: PLoS Genet. 2010 May 27;6(5):e1000969
references: 20523889
references: Cell. 2002 Aug 23;110(4):467-78
references: 12202036
references: Cancer Biol Ther. 2013 May;14(5):390-8
references: 23380592
references: PLoS Genet. 2012;8(3):e1002632
references: 22479211
references: Nature. 1964 Apr 4;202:100-1
references: 14166707
references: Science. 2004 Dec 24;306(5705):2267-70
references: 15618521
references: Oncogene. 1990 Nov;5(11):1629-35
references: 2267131
references: Dev Cell. 2010 Oct 19;19(4):491-505
references: 20951342
references: Cell. 2007 Sep 21;130(6):1120-33
references: 17889654
references: Mol Cell Biol. 1995 Aug;15(8):4125-35
references: 7623807
references: Dev Cell. 2013 May 28;25(4):388-401
references: 23725764
references: Dev Biol. 2010 Jan 15;337(2):303-12
references: 19900439
references: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2394-9
references: 22308401
references: J Exp Biol. 2007 Nov;210(Pt 21):3707-19
references: 17951411
references: PLoS One. 2011;6(7):e22278
references: 21811580
references: Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
references: 16936699
references: Nature. 2011 May 19;473(7347):326-35
references: 21593865
references: Dev Cell. 2011 Jan 18;20(1):109-22
references: 21238929
references: Int J Dev Biol. 2010;54(8-9):1375-82
references: 20712000
references: Biochem Biophys Res Commun. 2005 Oct 14;336(1):357-63
references: 16139248
references: Genes Dev. 2009 Oct 1;23(19):2307-19
references: 19762509
references: Dev Cell. 2008 Mar;14(3):388-98
references: 18258486
references: Nat Genet. 2007 Aug;39(8):1007-12
references: 17603483
references: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1394-9
references: 16432241
references: Trends Cardiovasc Med. 2012 Apr;22(3):55-61
references: 22863366
references: Curr Biol. 2006 Dec 19;16(24):2459-65
references: 17174922
references: Cell. 1996 Nov 15;87(4):651-60
references: 8929534
references: Cell Res. 2014 Mar;24(3):331-43
references: 24458094
references: Cancer Res. 1991 Sep 1;51(17):4570-4
references: 1678682
references: Mech Dev. 2001 Jun;104(1-2):49-60
references: 11404079
references: Cancer Cell. 2014 Feb 10;25(2):166-80
references: 24525233
references: Cell. 2005 Aug 12;122(3):421-34
references: 16096061
references: Genes Dev. 2007 Nov 1;21(21):2747-61
references: 17974916