Disease relevance of MYOCD

• METHODS: In this study, primary human mesenchymal stem cells and foreskin fibroblasts were transduced with human adenovirus vectors expressing the longest splice variant of the human myocardin gene (hAd5/F50.CMV.myocL) or with control vectors [1].
• Hypoxia induced the transdifferentiation of endothelial cells of vessels into smooth muscle-like cells which was regulated by myocardin [2].
• Myocardin induces cardiomyocyte hypertrophy [3].
• Adenovirus mediated overexpression of myocardin in A404 cells significantly increased LPP mRNA expression [4].

Psychiatry related information on MYOCD

• Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of Abeta a pathogenic pathway mediating arterial hypercontractility and CBF dysregulation, which are associated with Alzheimer's dementia [5].

High impact information on MYOCD

• One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development [6].
• Using a bioinformatics-based screen for unknown cardiac-specific genes, we identified a novel and highly potent transcription factor, named myocardin, that is expressed in cardiac and smooth muscle cells [7].
• Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor [7].
• Expression of a dominant negative mutant of myocardin in Xenopus embryos interferes with myocardial cell differentiation [7].
• Myocardin belongs to the SAP domain family of nuclear proteins and activates cardiac muscle promoters by associating with SRF [7].

Chemical compound and disease context of MYOCD

• Conversely, a dominant-negative mutant form of myocardin, which retains the ability to associate with SRF but is defective in transcriptional activation, blocks cardiomyocyte hypertrophy induced by hypertrophic agonists such as phenylephrine and leukemia inhibitory factor [3].

Biological context of MYOCD

• MYOCD overexpression in control human cerebral VSMC induced an AD-like hypercontractile phenotype and diminished both endothelial-dependent and -independent relaxation in the mouse aorta ex vivo [5].
• The SAP domain transcription factor myocardin plays a critical role in the transcriptional program regulating smooth muscle cell differentiation [8].
• Overexpressed HERP1 inhibited the myocardin-induced SMC marker gene expression in 10T1/2 cells [9].
• During embryonic development, the myocardin gene was expressed abundantly in a precise, developmentally regulated pattern in SMCs [10].
• Forced expression of myocardin transactivated multiple SMC-specific transcriptional regulatory elements in non-SMCs [10].

Anatomical context of MYOCD

• Whereas myocardin is expressed specifically in cardiac and smooth muscle cells, MRTF-A and -B are expressed in numerous embryonic and adult tissues [11].
• Together, these data were consistent with a model wherein MKL1 transduces signals from the cytoskeleton to the nucleus in SMCs and regulates SRF-dependent SMC differentiation autonomously or in concert with myocardin [8].
• Its ability to transactivate smooth muscle-specific genes has been firmly established in animal cells but its effect on heart muscle genes has been investigated less extensively and the consequences of ectopic myocardin expression in human cells are unknown [1].
• OBJECTIVE: Myocardin is a coactivator of serum response factor (SRF) required for vascular smooth muscle cell (VSMC) differentiation [9].
• Myocardin Sumoylation Transactivates Cardiogenic Genes in Pluripotent 10T1/2 Fibroblasts [12].

Associations of MYOCD with chemical compounds

• Here, we found that myocardin's activity was strongly enhanced by SUMO-1 via modification of a lysine residue primarily located at position 445 and that the conversion of this residue to arginine (K445R) impaired myocardin transactivation [12].
• Importantly, TRAM-34 completely blocked PDGF-BB-induced suppression of SMMHC, SMalphaA, smoothelin-B, and myocardin and inhibited PDGF-BB-stimulated migration by approximately 50% [13].
• 5. Zipzap/p200 activated the promoter of cardiac genes and potentiated the effect of myocardin on ANF promoter activity [14].
• We found that myocardin mRNA expression is upregulated significantly in the hypoxic pulmonary vessels and cultured cells but downregulated in PH with Sildenafil treatment [2].
• Interestingly, inactivation of RhoA with C3-exoenzyme or treatment with ROK inhibitors strongly inhibited myocardin mRNA expression in retinoic acid-treated A404 cells or human iliac vein SMCs [4].

Physical interactions of MYOCD

• Myocardin and myocardin-related transcription factors (MRTFs) interact with SRF and potently stimulate SRF-dependent transcription [15].

Regulatory relationships of MYOCD

• HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box [9].
• Consistent with a role in muscle specific gene expression, myocardin is specifically expressed in cardiac and smooth muscle cells while MKL1 and 2 are broadly expressed [16].
• Here we show that alternative splicing produces a cardiac-enriched isoform of myocardin containing a unique peptide sequence that confers the ability to interact with and stimulate the transcriptional activity of MEF2 [17].
• Myocardin-dependent hypertrophy can also be partially repressed by histone deacetylase 5, a transcriptional repressor of myocardin [3].

Other interactions of MYOCD

• MKL1 and myocardin physically associate via conserved leucine zipper domains [8].
• Expression of both HERP1 and myocardin was elevated in cultured VSMCs compared with medial SMC [9].
• Posttranslational modification of GATA4, another myocardin cofactor, by sumoylation strongly activated cardiogenic gene activity [12].
• We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays [18].
• Expression of cardiac transcription factors Mef2c, GATAs, myocardin and Nkx2.5 was not affected by cell expression of mutated MLC2v [19].

Analytical, diagnostic and therapeutic context of MYOCD

• METHODS AND RESULTS: Immunohistochemistry revealed that HERP1 and myocardin expression was localized to SMC in the neointima of balloon-injured rat aorta and in human coronary atherosclerotic lesions [9].
• Using Rbp-jkappa-deficient cells and site-specific mutagenesis of the SM-MHC gene, we show that such an induction is independent of the myocardin-serum response factor-CArG complex, but absolutely dependent on RBP-Jkappa, a major mediator of Notch signaling, and its cognate binding sequence [20].
• Myocardin and relative markers were investigated in animal models and cultured endothelial cells [2].
• Immunohistochemistry and immunofluorescence were used to show the expression of smooth muscle alpha-actin (SMA), in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR) were performed respectively to detect the myocardin and SMA expression at mRNA levels [2].
• Consistent with a role for myocardin as a transducer of hypertrophic signals, forced expression of myocardin in cardiomyocytes is sufficient to substitute for hypertrophic signals and induce cardiomyocyte hypertrophy and the fetal cardiac gene program [3].

References