Bradykinin B1 receptor blocks PDGF-induced mitogenesis by prolonging ERK activation and increasing p27Kip1.
Am J Physiol Cell Physiol
; 283(1): C193-203, 2002 Jul.
Article
em En
| MEDLINE
| ID: mdl-12055088
ABSTRACT
The mechanism by which the bradykinin B1 receptor (B1R) inhibits platelet-derived growth factor (PDGF)-stimulated proliferation was investigated in cultured rat mesenteric arterial smooth muscle cells. The B1R agonist des-Arg9-bradykinin (DABK) was found to inhibit PDGF-mediated activation of the cyclin E-cyclin-dependent kinase 2 (Cdk2) complex and to prevent hyperphosphorylation of retinoblastoma protein. DABK did not inhibit upregulation of cyclin E expression but increased expression of the Cdk2 inhibitor p27Kip1 and the association of p27Kip1 with the cyclin E-Cdk2 complex. In addition, DABK inhibited the PDGF-stimulated expression of cyclin D that would otherwise siphon p27Kip1 away from inhibition of cyclin E-Cdk2. The signaling mechanism by which DABK regulated p27Kip1 was explored. DABK was found to stimulate the activity of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) and to prolong activation of MEK and ERK by PDGF. Inhibition of ERK activation with the MEK inhibitors PD-98059 and U-0126 as well as the Src family kinase inhibitor PP2 completely blocked the effect of DABK to increase p27Kip1 and partially reversed the DABK-mediated inhibition of PDGF-stimulated proliferation. These studies demonstrate that the B1R inhibits PDGF-stimulated mitogenesis in part by prolonged activation of ERK leading to increased expression of p27Kip1.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Derivado de Plaquetas
/
Bradicinina
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Receptores da Bradicinina
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Proteínas de Ciclo Celular
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Proteínas Quinases Ativadas por Mitógeno
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Proteínas Supressoras de Tumor
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Quinases relacionadas a CDC2 e CDC28
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Mitose
Limite:
Animals
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article