Role of c-fos and E2F in the induction of cyclin A transcription and vascular smooth muscle cell proliferation.
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 of vascular proliferative disorders.
Sylvester
A M
AM
Department of Medicine (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Chen
D
D
Krasinski
K
K
Andrés
V
V
D051698:Activating Transcription Factor 2; D017130:Angioplasty; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D019925:Cyclin A / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000098:blood supply* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D018631:ras Proteins / Q000378:metabolism
D051698:Activating Transcription Factor 2; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D004247:DNA; D008156:Luciferases; D018631:ras Proteins; D001973:Bromodeoxyuridine