Role of c-fos and E2F in the Induction of Cyclin A Transcription and Vascular Smooth Muscle Cell Proliferation

Abstract

Excessive proliferation of vascular smooth muscle cells (VSMCs) contributes to vessel renarrowing after angioplasty. Here we investigated the transcriptional regulation of the cyclin A gene, a key positive regulator of S phase that is induced after angioplasty. We show that Ras-dependent mitogenic signaling is essential for the normal stimulation of cyclin A promoter activity and DNA synthesis in VSMCs. Overexpression of the AP-1 transcription factor c-fos can circumvent this requirement via interaction with the cAMP-responsive element (CRE) in the cyclin A promoter. Moreover, c-fos overexpression in serum-starved VSMCs results in the induction of cyclin A promoter activity in a CRE-dependent manner, and increased binding of endogenous c-fos protein to the cyclin A CRE precedes the onset of DNA replication in VSMCs induced by serum in vitro and by angioplasty in vivo. We also show that E2F function is essential for both serum- and c-fos-dependent induction of cyclin A expression. Taken together, these findings suggest that c-fos and E2F are important components of the signaling cascade that link Ras activity to cyclin A transcription in VSMCs. These studies illustrate a novel link between the transcriptional and cell cycle machinery that may be relevant to the pathogenesis