Abstract
Elevated catecholamines in the heart evoke transcriptional activation of the Myocyte Enhancer Factor (MEF) pathway to induce a cellular response known as pathological myocardial hypertrophy. We have discovered that the A-Kinase Anchoring Protein (AKAP)-Lbc is upregulated in hypertrophic cardiomyocytes. It coordinates activation and movement of signaling proteins that initiate MEF2-mediated transcriptional reprogramming events. Live-cell imaging, fluorescent kinase activity reporters, and RNA interference techniques show that AKAP-Lbc couples activation of protein kinase D (PKD) with the phosphorylation-dependent nuclear export of the class II histone deacetylase HDAC5. These studies uncover a role for AKAP-Lbc in which increased expression of the anchoring protein selectively amplifies a signaling pathway that drives cardiac myocytes toward a pathophysiological outcome.
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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14-3-3 Proteins / metabolism
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A Kinase Anchor Proteins / genetics
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A Kinase Anchor Proteins / metabolism
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A Kinase Anchor Proteins / physiology*
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Active Transport, Cell Nucleus
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Animals
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COS Cells
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Cardiomegaly / metabolism*
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Cell Line
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Chlorocebus aethiops
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Gene Expression Regulation
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism
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Guanine Nucleotide Exchange Factors / physiology*
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Heart Ventricles / drug effects
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Histone Deacetylases / metabolism
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Humans
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MEF2 Transcription Factors
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Minor Histocompatibility Antigens
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Models, Biological
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Myocytes, Cardiac / pathology
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Myogenic Regulatory Factors / metabolism
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Phenylephrine / pharmacology
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Phosphorylation
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Protein Kinase C / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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RNA Interference
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Rats
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Signal Transduction*
Substances
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14-3-3 Proteins
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A Kinase Anchor Proteins
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AKAP13 protein, human
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Guanine Nucleotide Exchange Factors
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MEF2 Transcription Factors
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Minor Histocompatibility Antigens
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Myogenic Regulatory Factors
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Proto-Oncogene Proteins
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Phenylephrine
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protein kinase D
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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Hdac5 protein, rat
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Histone Deacetylases