Possible mechanism of GATA4 inhibiting myocardin activity during cardiac hypertrophy

Myocardin is an important factor that regulates cardiac hypertrophy, and its activity can be regulated by GATA4. However, the molecular mechanism of the above process remains unclear. This paper presents three kinds of possible molecular mechanisms of GATA4 inhibiting myocardin activity in the process of cardiac hypertrophy. First, a competitive combination of GATA4 and SRF with myocardin could reduce the formation of the myocardin-SRF-CarG box complex when GATA4 was overexpressed. Second, overexpression of GATA4 could inhibit the combination of myocardin and p300 and downregulate acetylated myocardin levels. Finally, GATA4 could upregulate the phosphorylation of myocardin protein upon activation of the ERK pathway. These findings may provide insight into the function of GATA4 and myocardin in the occurrence and development of cardiac hypertrophy.     

Myocardin sumoylation transactivates cardiogenic genes in pluripotent 10T1/2 fibroblasts

Myocardin, a serum response factor (SRF)-dependent cofactor, is a potent activator of smooth muscle gene activity but a poor activator of cardiogenic genes in pluripotent 10T1/2 fibroblasts. Posttranslational modification of GATA4, another myocardin cofactor, by sumoylation strongly activated cardiogenic gene activity. 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. PIAS1 was involved in governing myocardin activity via its E3 ligase activity that stimulated myocardin sumoylation on an atypical sumoylation site(s) and by its physical association with myocardin. Myocardin initiated the expression of cardiac muscle-specified genes, such as those encoding cardiac alpha-actin and alpha-myosin heavy chain, in an SRF-dependent manner in 10T1/2 fibroblasts, but only in the presence of coexpressed SUMO-1/PIAS1. Thus, SUMO modification acted as a molecular switch to promote myocardin's role in cardiogenic gene expression.     

Myocardin in Tumor Suppression and Myofibroblast Differentiation

The malignant transformation process is associated with defects in cell cycle regulation and disruption of the normal differentiation programs in both neoplastic and adjacent stroma cells. However, the relationships between the cell cycle, differentiation and cancer are very complex and tissue specific. Recently we have demonstrated a previously unrecognized role in human carcinogenesis for the important regulator of cardiac and smooth muscle differentiation, myocardin. Myocardin expression is frequently repressed during human malignant transformation contributing to a differentiation defect in the premalignant mesenchymal cells. TGFβ treatment, serum deprivation and intact contact inhibition response all contribute to myocardin induction and differentiation. Positive regulation of myocardin mRNA levels and activity by the p16/Rb pathway provides a molecular link between cell cycle and differentiation defects during cancer development. In addition, we show that myocardin represses its own expression in human fibroblasts. This negative autoregulatory loop might be potentially important for restraining myocardin activity and allowing reversibility of fibroblast-myofibroblast phenotypic conversion.Here we discuss the emerging role of myocardin in tumor suppression as well as novel aspects of its regulation in normal and malignant conditions.