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The CRM1 nuclear export receptor controls pathological cardiac gene expression
The CRM1 nuclear export receptor controls pathological cardiac gene expression
3716
Diverse pathological insults trigger a cardiac remodeling process during which myocytes undergo hypertrophy, with consequent decline in cardiac function and eventual heart failure. Multiple transcriptional regulators of pathological cardiac hypertrophy are controlled at the level of subcellular distribution. For example, prohypertrophic transcription factors belonging to the nuclear factor of activated T cells (NFAT) and GATA families are subject to CRM1-dependent nuclear export but are rapidly relocalized to the nucleus in response to cues for hypertrophic growth. Here, we demonstrate that the antihypertrophic chromatin-modifying enzyme histone deacetylase 5 (HDAC5) is shuttled out of the cardiomyocyte nucleus via a CRM1-mediated pathway in response to diverse signals for hypertrophy. CRM1 antagonists block the agonist-mediated nuclear export of HDAC 5 and repress pathological gene expression and associated hypertrophy of cultured cardiomyocytes. Conversely, CRM1 activity is dispensable for nonpathological cardiac gene activation mediated by thyroid hormone and insulin-like growth factor 1, agonists that fail to trigger the nuclear export of HDAC5. These results suggest a selective role for CRM1 in derepression of pathological cardiac genes via its neutralizing effects on antihypertrophic factors such as HDAC5. Pharmacological approaches targeting CRM1-dependent nuclear export in heart muscle may have salutary effects on cardiac function by suppressing maladaptive changes in gene expression evoked by stress signals.
Harrison BC, Roberts CR, Hood DB, Sweeney M, Gould JM, Bush EW, McKinsey TA
Molecular and cellular biology
2004-12-01 00:00
24
24
10636-49
Adenoviridae,Adenylate Kinase,Adhesins, Bacterial,Animals,Animals, Newborn,Antibodies, Monoclonal,Atrial Natriuretic Factor,Cardiomegaly,Cell Nucleus,Cell Size,Cell Survival,Cells, Cultured,Dose-Response Relationship, Drug,Enzyme-Linked Immunosorbent Assay,Fluoresceins,Fluorescent Dyes,Gene Expression Regulation,Green Fluorescent Proteins,Heart Ventricles,Histone Deacetylases,Immunoblotting,Karyopherins,Microscopy, Fluorescence,Myocytes, Cardiac,Precipitin Tests,RNA,Rats,Rats, Sprague-Dawley,Receptors, Cytoplasmic and Nuclear,Adhesins, Bacterial,Antibodies, Monoclonal,Fluoresceins,Fluorescent Dyes,Karyopherins,Receptors, Cytoplasmic and Nuclear,exportin 1 protein,Green Fluorescent Proteins,calcein AM,RNA,Atrial Natriuretic Factor,Adenylate Kinase,Histone Deacetylases
Myogen Inc., 7575 W. 103rd Ave., Westminister, CO 80021, USA. timothy.mckinsey@myogen.com
Mol. Cell. Biol.
0270-7306
10.1128/MCB.24.24.10636-10649.2004
24/24/10636
0
False
15572669
