The Transcriptional Co-activators CREB-binding Protein (CBP) and p300 Play a Critical Role in Cardiac Hypertrophy That Is Dependent on Their Histone Acetyltransferase Activity*

The CBP and p300 proteins are transcriptional co-activators that are involved in a variety of transcriptional pathways in development and in response to specific signaling pathways. We have previously demonstrated that the ability of both these factors to stimulate transcription is greatly enhanced by treatment of cardiac cells with the hypertrophic agent phenylephrine (PE). Here, we show that inhibition of either CBP or p300 with antisense or dominant negative mutant constructs inhibits PE-induced hypertrophy as assayed by atrial naturetic protein production, cardiac cell protein:DNA ratio and cell size. Furthermore, we show that overexpression of CBP or p300 can induce hypertrophy and that this effect requires their histone acetyltransferase (HAT) activity. Moreover, we show that PE can directly enhance CBP HAT activity and that artificial enhancement of HAT activity is sufficient to induce hypertrophy. Hence, CBP and p300 play an essential role in hypertrophy induced by PE, and this effect is mediated via PE-induced enhancement of their HAT activity. This is the first time a role for these factors, and their HAT activity, in hypertrophy has been directly demonstrated.

[1]  C. Stevens,et al.  Cardiac abnormalities in the Rubinstein-Taybi syndrome. , 1995, American journal of medical genetics.

[2]  C. Allis,et al.  Signaling to Chromatin through Histone Modifications , 2000, Cell.

[3]  D. Glover.  DNA cloning : a practical approach , 1985 .

[4]  David Newsome,et al.  Gene Dosage–Dependent Embryonic Development and Proliferation Defects in Mice Lacking the Transcriptional Integrator p300 , 1998, Cell.

[5]  D. Ayer,et al.  Histone deacetylases: transcriptional repression with SINers and NuRDs. , 1999, Trends in cell biology.

[6]  D. Livingston,et al.  Interaction and functional collaboration of p300/CBP and bHLH proteins in muscle and B-cell differentiation. , 1996, Genes & development.

[7]  M van Bilsen,et al.  Growth and hypertrophy of the heart: towards an understanding of cardiac specific and inducible gene expression. , 1993, Cardiovascular research.

[8]  S. Bhalla,et al.  Cooperative Activation by GATA-4 and YY1 of the Cardiac B-type Natriuretic Peptide Promoter* , 2001, The Journal of Biological Chemistry.

[9]  J. Girault,et al.  Histone acetyltransferase activity of CBP is controlled by cycle-dependent kinases and oncoprotein E1A , 1998, Nature.

[10]  A. Harel-Bellan,et al.  Phosphorylation by p44 MAP Kinase/ERK1 stimulates CBP histone acetyl transferase activity in vitro. , 1999, Biochemical and biophysical research communications.

[11]  B. Markham,et al.  p300 Functions as a Coactivator of Transcription Factor GATA-4* , 2001, The Journal of Biological Chemistry.

[12]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[13]  Antonio Giordano,et al.  p300 and CBP: Partners for life and death , 1999, Journal of cellular physiology.

[14]  N. Shiama.  The p300/CBP family: integrating signals with transcription factors and chromatin. , 1997, Trends in cell biology.

[15]  K. Webster,et al.  Adenovirus E1A Inhibits Cardiac Myocyte-specific Gene Expression through Its Amino Terminus* , 1997, The Journal of Biological Chemistry.

[16]  L. Kedes,et al.  Proteasome-Mediated Degradation of the Coactivator p300 Impairs Cardiac Transcription , 2000, Molecular and Cellular Biology.

[17]  Y. Fujio,et al.  Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes. , 1998, Circulation.

[18]  J. Workman,et al.  The many HATs of transcription coactivators. , 2000, Trends in biochemical sciences.

[19]  B. Howard,et al.  The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases , 1996, Cell.

[20]  J. Molkentin,et al.  Angiotensin II type1a receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[21]  K. Chien,et al.  Co-regulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during alpha-adrenergic stimulation of neonatal rat ventricular cells. Identification of cis sequences within an embryonic and a constitutive contractile protein gene which mediate inducible expression. , 1991, The Journal of biological chemistry.

[22]  A. Bird,et al.  Histone deacetylases: silencers for hire. , 2000, Trends in biochemical sciences.

[23]  R. Kitsis,et al.  Transcriptional Coactivator p300 Stimulates Cell Type-specific Gene Expression in Cardiac Myocytes* , 1997, The Journal of Biological Chemistry.

[24]  R. A. Hunt,et al.  Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3 : an autocrine loop for hypertrophy. , 2000, Hypertension.

[25]  E. Lalli,et al.  Signal transduction and gene regulation: the nuclear response to cAMP. , 1994, The Journal of biological chemistry.

[26]  R. Janknecht,et al.  The Ewing's sarcoma gene product functions as a transcriptional activator. , 2001, Cancer research.

[27]  S. Sasayama,et al.  Phosphorylation of GATA-4 Is Involved in α1-Adrenergic Agonist-responsive Transcription of the Endothelin-1 Gene in Cardiac Myocytes* , 2000, The Journal of Biological Chemistry.

[28]  J H RUBINSTEIN,et al.  Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. , 1963, American journal of diseases of children.

[29]  A. Giordano,et al.  The Transcriptional Co-activators CBP and p300 Are Activated via Phenylephrine through the p42/p44 MAPK Cascade* , 2002, The Journal of Biological Chemistry.

[30]  A. Harel-Bellan,et al.  CBP/p300 histone acetyl-transferase activity is important for the G1/S transition , 2000, Oncogene.

[31]  R. Goodman,et al.  CBP/p300 in cell growth, transformation, and development. , 2000, Genes & development.

[32]  R. Hennekam,et al.  Rubinstein-Taybi syndrome in The Netherlands. , 2005, American journal of medical genetics. Supplement.

[33]  L. Bordoli,et al.  Functional analysis of the p300 acetyltransferase domain: the PHD finger of p300 but not of CBP is dispensable for enzymatic activity. , 2001, Nucleic acids research.

[34]  M. Pfeffer,et al.  Atrial natriuretic factor gene expression in ventricles of rats with spontaneous biventricular hypertrophy. , 1988, The Journal of clinical investigation.

[35]  Raoul C. M. Hennekam,et al.  Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP , 1995, Nature.

[36]  M. Siddiqui,et al.  Signal transduction and activator of transcription (STAT) protein-dependent activation of angiotensinogen promoter: a cellular signal for hypertrophy in cardiac muscle. , 1998, Proceedings of the National Academy of Sciences of the United States of America.