Abstract
Postnatal cardiac myocytes respond to diverse signals by hypertrophic growth and activation of a fetal gene program. In an effort to discover regulators of cardiac hypertrophy, we performed a eukaryotic expression screen for activators of the atrial natriuretic factor (ANF) gene, a cardiac-specific marker of hypertrophic signaling. We discovered that a family of transcriptional coactivators, called CAMTAs, promotes cardiomyocyte hypertrophy and activates the ANF gene, at least in part, by associating with the cardiac homeodomain protein Nkx2-5. The transcriptional activity of CAMTAs is governed by association with class II histone deacetylases (HDACs), which negatively regulate cardiac growth. Mice homozygous for a mutation in a CAMTA gene are defective in cardiac growth in response to pressure overload and neurohumoral signaling, whereas mice lacking HDAC5, a class II HDAC, are sensitized to the prohypertrophic actions of CAMTA. These findings reveal a transcriptional regulatory mechanism that modulates cardiac growth and gene expression by linking hypertrophic signals to the cardiac genome.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Atrial Natriuretic Factor / genetics
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Atrial Natriuretic Factor / metabolism
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COS Cells
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / isolation & purification
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Calcium-Binding Proteins / metabolism*
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Calmodulin-Binding Proteins / genetics
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Calmodulin-Binding Proteins / isolation & purification
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Calmodulin-Binding Proteins / metabolism*
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Cardiomegaly / genetics
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Cardiomegaly / metabolism
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Cardiomegaly / physiopathology
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Chlorocebus aethiops
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Gene Expression Regulation, Developmental / physiology
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Genetic Testing
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Heart / embryology*
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Heart / growth & development
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Mice
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Mice, Knockout
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Mutation / genetics
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Myocardium / cytology
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Myocardium / metabolism*
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / metabolism*
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Protein Kinase C / metabolism
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Protein Structure, Tertiary
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / physiology
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Trans-Activators / genetics
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Trans-Activators / isolation & purification
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcriptional Activation / physiology
Substances
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CAMTA2 protein, mouse
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Calcium-Binding Proteins
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Calmodulin-Binding Proteins
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins
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Nkx2-5 protein, mouse
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Trans-Activators
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Transcription Factors
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Atrial Natriuretic Factor
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protein kinase D
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Protein Kinase C
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Hdac5 protein, mouse
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Histone Deacetylases