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. TGFbeta 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.
Shats
Igor
I
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Milyavsky
Michael
M
Cholostoy
Alina
A
Brosh
Ran
R
Rotter
Varda
V
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009130:Muscle, Smooth / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D000099251:Myocardin
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099251:Myocardin