Role of E2F and ERK1/2 in STI571-mediated smooth muscle cell growth arrest and cyclin A transcriptional repression.
Platelet-derived growth factor (PDGF) ligand and receptors (PDGF-R) activate smooth muscle cell (SMC) proliferation, a key event during vascular obstructive disease. The PDGF-R tyrosine kinase inhibitor STI571 attenuates SMC proliferation and experimental neointimal thickening. Here, we investigated the molecular mechanisms underlying STI571-dependent SMC growth arrest. STI571 abrogates PDGF-BB-dependent cyclin D1 and cyclin A protein expression and inhibits transcriptional activation of reporter genes driven by the human cyclin A gene promoter. Repression of cyclin A promoter activity by STI571 requires a functional E2F-binding site, and forced expression of E2F overrides this inhibitory effect. Moreover, STI571 inhibits E2F DNA-binding activity in SMCs. We also found that STI571 abrogates PDGF-BB-dependent activation of extracellular-regulated kinase 1 and 2 (ERK1/2), and forced activation of these factors impaired STI571-dependent inhibition of both cyclin A promoter activity and SMC proliferation. Thus, E2F and ERK1/2 play an important role in STI571-mediated SMC growth arrest and cyclin A transcriptional repression. These findings may have importance in the development of novel therapeutic strategies for the treatment of neointimal hyperplasia.
Sanz-González
Silvia M
SM
Loboratory of Vascular Biology, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientificas, Valencia, Spain.
Castro
Claudia
C
Pérez
Paloma
P
Andrés
Vicente
V
D000818:Animals; D000077214:Becaplermin; D001549:Benzamides; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D001549:Benzamides; D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D012097:Repressor Proteins; D014157:Transcription Factors; D019938:Cyclin D1; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases