2024-03-28T19:27:58Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/368872019-04-18T07:20:55Zcom_10261_109com_10261_1col_10261_362
Role of E2F and ERK1/2 in STI571-mediated smooth muscle cell growth arrest and cyclin A transcriptional repression
Sanz-González, Silvia M.
Castro, Claudia
Pérez, Paloma
Andrés, Vicente
STI571
Smooth muscle cell
Cyclin A
ERK
E2F
8 páginas, 6 figuras.-- El docuemnto en word es la versión post-print.
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.
Work in
the laboratory of V.A. is supported in part by grants from the Ministerio
de Ciencia y Tecnología of Spain and Fondo Europeo de
Desarrollo Regional (SAF2001-2358, SAF2002-1443), from Instituto
de Salud Carlos III (ISCIII) (Red de Centros C03/01), and from Genera-litat Valenciana (GRUPOS03/072). S.M.S.-G. is a research
fellow of the ISCIII. C.C. has been supported by research fellowships
from the Agencia Española de Cooperación Internacional and from
the ISCIII.
Peer reviewed
2011-06-16T09:51:08Z
2011-06-16T09:51:08Z
2004-05-14
artículo
http://purl.org/coar/resource_type/c_6501
Biochemical and Biophysical Research Communications 317(4): 972-979 (2004)
0006-291X
http://hdl.handle.net/10261/36887
10.1016/j.bbrc.2004.03.143
en
http://dx.doi.org/10.1016/j.bbrc.2004.03.143
open
Elsevier