P53 Promotes Retinoid Acid-induced Smooth Muscle Cell Differentiation by Targeting Myocardin.

Abstract

TP53 is a widely studied tumor suppressor gene that controls various cellular functions, including cell differentiation. However, little is known about its functional roles in smooth muscle cells (SMCs) differentiation from embryonic stem cells (ESCs). SMC differentiation is at the heart of our understanding of vascular development, normal blood pressure homeostasis, and the pathogenesis of vascular diseases such as atherosclerosis, hypertension, restenosis, as well as aneurysm. Using retinoid acid (RA)-induced SMC differentiation models, we observed that p53 expression is increased during in vitro differentiation of mouse ESCs into SMCs. Meanwhile, suppression of p53 by shRNA reduced RA-induced SMC differentiation. Mechanistically, we have identified for the first time that Myocardin, a transcription factor that induces muscle cell differentiation and muscle-specific gene expression, is the direct target of p53 by bioinformatic analysis, luciferase reporter assay, and chromatin immunoprecipitation approaches. Moreover, in vivo SMC-selective p53 transgenic overexpression inhibited injury-induced neointimal formation. Taken together, our data demonstrate that p53 and its target gene, Myocardin, play regulatory roles in SMC differentiation. This study may lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of vascular diseases.