Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The association of transcriptional coactivators with DNA-binding proteins provides an efficient mechanism to expand and modulate genetic information encoded within the genome. Myocardin-related transcription factors (MRTFs), including myocardin, MRTF-A/MKL1/MAL, and MRTF-B/MKL2, comprise a family of related transcriptional coactivators that physically associate with the MADS box transcription factor, serum response factor, and synergistically activate transcription. MRTFs transduce cytoskeletal signals to the nucleus, activating a subset of serum response factor-dependent genes promoting myogenic differentiation and cytoskeletal organization. MRTFs are multifunctional proteins that share evolutionarily conserved domains required for actin-binding, homo- and heterodimerization, high-order chromatin organization, and transcriptional activation. Mice harboring loss-of-function mutations in myocardin, MRTF-A, and MRTF-B, respectively, display distinct phenotypes, including cell autonomous defects in vascular smooth muscle cell and myoepithelial cell differentiation and function. This article reviews the molecular basis of MRTF function with particular focus on the role MRTFs play in regulating cardiovascular patterning, vascular smooth muscle cell and cardiomyocyte differentiation and in the pathogenesis of congenital heart disease and vascular proliferative syndromes.
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PMID:Myocardin-related transcription factors: critical coactivators regulating cardiovascular development and adaptation. 1736 9

Myocardin (MYOCD) is a transcriptional co-activator that promotes cardiac or smooth muscle gene programs through its interaction with myocyte-enhancing factor (MEF2) or serum-response factor (SRF). Isoforms of MYOCD with a truncated amino terminus show increased activity when compared with those with the full-length amino terminus, but how this is achieved remains unknown. We identified a rare human sequence variation in MYOCD in a patient with congenital heart disease that resulted in a missense mutation at codon 259 (K259R). This variation created a hypomorphic cardiac isoform with impaired SRF binding and transactivation capacity but did not impair the smooth muscle isoform of MYOCD, which lacks the amino terminus. Consistent with differential effects of the amino terminus on the K259R mutation, we found that the cardiac-specific amino terminus acted in an autoinhibitory fashion to bind MYOCD via specific negatively charged residues and thereby repressed SRF-dependent MYOCD activity. This effect was exaggerated in the MYOCD-K259R mutant. The amino terminus was sufficient to impair MYOCD-dependent fibroblast conversion into smooth muscle cells as well as cardiomyocyte hypertrophy. These findings identify a novel mechanism that regulates levels of MYOCD-dependent activation of the SRF genetic program differentially in cardiac and smooth muscle.
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PMID:A rare human sequence variant reveals myocardin autoinhibition. 1885 65