Inactivation of myocardin and p16 during malignant transformation contributes to a differentiation defect.
Myocardin is known as an important transcriptional regulator in smooth and cardiac muscle development. Here we found that myocardin is frequently repressed during human malignant transformation, contributing to a differentiation defect. We demonstrate that myocardin is a transcriptional target of TGFbeta required for TGFbeta-mediated differentiation of human fibroblasts. Serum deprivation, intact contact inhibition response, and the p16ink4a/Rb pathway contribute to myocardin induction and differentiation. Restoration of myocardin expression in sarcoma cells results in differentiation and inhibition of malignant growth, whereas inactivation of myocardin in normal fibroblasts increases their proliferative potential. Myocardin expression is reduced in multiple types of human tumors. Collectively, our results demonstrate that myocardin is an important suppressive modifier of the malignant transformation process.
Milyavsky
Michael
M
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Shats
Igor
I
Cholostoy
Alina
A
Brosh
Ran
R
Buganim
Yosef
Y
Weisz
Lilach
L
Kogan
Ira
I
Cohen
Merav
M
Shatz
Maria
M
Madar
Shalom
S
Kalo
Eyal
E
Goldfinger
Naomi
N
Yuan
Jun
J
Ron
Shulamit
S
MacKenzie
Karen
K
Eden
Amir
A
Rotter
Varda
V
D015153:Blotting, Western; D002448:Cell Adhesion; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000196:embryology; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000099251:Myocardin
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000099251:Myocardin