cAMP response element-binding protein content is a molecular determinant of smooth muscle cell proliferation and migration

We hypothesized that cAMP response element-binding protein (CREB) could fun ction as a molecular determinant of smooth muscle cell fate. In arterial se ctions from the systemic and pulmonary circulation, CREB content was high i n proliferation-resistant medial subpopulations of smooth muscle cells and low in proliferation-prone regions. In vessels from neonatal calves exposed to chronic hypoxia, CREB content was depleted and smooth muscle cell (SMC) proliferation was accelerated. Induction of quiescence by serum deprivatio n in culture led to increased CREB content. Highly proliferative SMC in cul ture were observed to have low CREB content. Exposure to proliferative stim uli such as hypoxia or platelet-derived growth factor decreased SMC CREB co ntent. Assessment of CREB gene transcription by nuclear run-on analysis and transcription from a CREB promoter-luciferase construct indicate that CREB levels in SMC are in part controlled at the level of transcription. Overex pression of wild type or constitutively active CREB in primary cultures of SMC arrested cell cycle progression. Additionally, expression of constituti vely active CREB decreased both proliferation and chemokinesis. Consistent with these functional properties, active CREB decreased the expression of m ultiple cell cycle regulatory genes, as well as genes encoding growth facto rs, growth factor receptors, and cytokines. Our data suggest a unique mode of cellular phenotype determination at the level of the nuclear content of CREB.