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Role of E2F and ERK1/2 in STI571-mediated smooth muscle cell growth arrest and cyclin A transcriptional repression

AuthorsSanz-González, Silvia M. ; Castro, Claudia; Pérez, Paloma ; Andrés, Vicente
Smooth muscle cell
Cyclin A
Issue Date14-May-2004
CitationBiochemical and Biophysical Research Communications 317(4): 972-979 (2004)
AbstractPlatelet-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.
Description8 páginas, 6 figuras.-- El docuemnto en word es la versión post-print.
Publisher version (URL)http://dx.doi.org/10.1016/j.bbrc.2004.03.143
Appears in Collections:(IBV) Artículos
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