Disease relevance of Myocd

• Inhibition of myocardin function in the teratocarcinoma cell line P19CL6 prevented differentiation into cardiac myocytes after dimethyl sulfoxide treatment [1].
• These data provide a model wherein the respiratory epithelium responds to hypoxia via HIF-1alpha-dependent regulation of MK, enhancing myocardin expression to influence pulmonary vascular gene expression [2].

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 [3].

High impact information on Myocd

• Dominant-negative variants of the SRF cofactor megakaryocytic acute leukemia (MAL) severely impeded neurite outgrowth and guidance [4].
• However, these substitutions significantly attenuated injury-induced downregulation of the mutant transgene under conditions where SRF expression was increased but expression of myocardin, a smooth muscle-selective SRF coactivator, was decreased [5].
• Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype [3].
• The phenotype of MRTF-B mutant mice is distinct from that of mice lacking myocardin, revealing unique roles for these serum response factor coactivators in the development of different subsets of smooth muscle cells in vivo [6].
• Serum response factor (SRF) controls the transcription of muscle genes by recruiting a variety of partner proteins, including members of the myocardin family of transcriptional coactivators [7].

Biological context of Myocd

• Mutagenesis studies indicate that the C-terminal transactivation domains of Myocd and Smad3 are required for their functional synergy [8].
• These results reveal a novel regulatory mechanism whereby Myocd participates in TGF-beta1 signal pathway through direct interaction with Smad3, which binds to the SBEs [8].
• Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin [9].
• Here, we show that myocardin induces the acetylation of nucleosomal histones surrounding SRF-binding sites in the control regions of smooth muscle genes [9].
• Conversely, class II histone deacetylases interact with a domain of myocardin distinct from the p300-binding domain and suppress smooth muscle gene activation by myocardin [9].

Anatomical context of Myocd

• This is the first demonstration that Myocd can act as a transcriptional coactivator of the smooth muscle regulatory network in a CArG box-independent manner [8].
• We observed the absence of myogenic alpha-actins, SM22alpha, and myocardin expression and the failure to form beating cardiac myocytes in aggregated SRF null embryonic stem cells, whereas the appearance of transcription factors Nkx2-5 and GATA4 were unaffected [10].
• Unlike myocardin, which is expressed specifically in smooth and cardiac muscle, MRTF-B is expressed in a wide variety of tissues [11].
• The serum response factor coactivator myocardin is required for vascular smooth muscle development [12].
• These findings reveal an essential role for the partnership of SRF and myocardin-related transcription factors in the control of skeletal muscle growth and maturation in vivo [7].

Associations of Myocd with chemical compounds

• 5. Zipzap/p200 activated the promoter of cardiac genes and potentiated the effect of myocardin on ANF promoter activity [13].
• The aim of the present study was to determine whether myocardin, a SMC-selective cofactor of serum response factor (SRF), contributed to Ang II-induced increases in SM alpha-actin transcription [14].
• Stable overexpression of dominant-negative myocardin in A404 cells resulted in impaired induction of SM alpha-actin and SM-MHC by all trans-retinoic acid but had no effect on induction of smoothelin-B and aortic carboxypeptidase-like protein expression [15].
• Glutathione S-transferase pull-down assays demonstrated that TDG binds to a region of myocardin that includes the SRF binding domain [16].

Physical interactions of Myocd

• Elements 3' of the CArG box in the c-fos promoter act in concert with the ets binding site to block the ability of myocardin to activate the promoter [17].

Regulatory relationships of Myocd

• Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis [1].
• Taken together, these results demonstrate that Notch signaling represses myocardin-dependent SMC transcription [18].
• Data from these experiments demonstrated that the ets binding site in the c-fos promoter partially blocks the activation of this promoter by myocardin [17].
• Cotransfection studies in SMCs revealed that myocardin induced the activity of multiple SMC marker gene promoters including SM alpha-actin, SM-myosin heavy chain, and SM22alpha by 9- to 60-fold in a CArG-dependent manner, whereas myocardin short interfering RNA markedly decreased activity of these promoters [19].
• GATA-6 did not interfere with the serum-response factor-stimulated promoter activity but blocked myocardin-induced activation of the telokin promoter [20].

Other interactions of Myocd

• Transient-cotransfection analysis showed that Nkx2.5 transactivates the myocardin promoter [1].
• Immunopreciptiation assays reveal that Myocd and Smad3 directly interact both in vitro and in vivo [8].
• Importantly, Myocd cooperates with Smad3 to activate the wild-type SM22alpha, SM myosin heavy chain, and SMalpha-actin promoters; they also activate the CArG box-mutated SM22alpha promoter as well as the CArG box-independent aortic carboxypeptidase-like protein promoter [8].
• MK increased muscularization of small pulmonary arteries, increasing alpha-smooth muscle actin and caldesmon staining and the expression of myocardin [2].
• The present studies showed induction of the SMC-selective genes smooth muscle alpha-actin (SMalphaA), SM22alpha, myocardin, smoothelin-B, and smooth muscle myosin heavy chain (SMMHC) within a mouse ESC-EB model system [21].

Analytical, diagnostic and therapeutic context of Myocd

• Real time RT-PCR analyses showed no significant difference in expression of SM-alpha-actin, SM myosin heavy chain, and myocardin in various SM tissues from all three genotypes, suggesting that knockout of AT(2)R had no effect on subsequent SMC differentiation [22].
• Electrophoretic mobility shift assay showed that myocardin and Ang II, respectively, increased formation of a SMC-specific CArG-SRF-myocardin higher order complex [14].
• However, Ang II had no effect on binding between myocardin and SRF as determined by a mammalian two-hybrid assay, suggesting that Ang II-induced increases in formation of CArG-SRF-myocardin complex was the result of increased SRF binding to CArG elements and increased myocardin expression [14].
• Finally, chromatin immunoprecipitation analyses, together with cell culture studies, suggested that myocardin selectively enhanced SRF binding to degenerate versus consensus CArG elements [5].

References