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首页> 外文期刊>American Journal of Physiology >Bradykinin B1 receptor blocks PDGF-induced mitogenesis by prolonging ERK activation and increasing p27Kip1.
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Bradykinin B1 receptor blocks PDGF-induced mitogenesis by prolonging ERK activation and increasing p27Kip1.

机译：缓激肽B1受体通过延长ERK激活并增加p27Kip1来阻断PDGF诱导的有丝分裂。

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摘要

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.
机译：在培养的大鼠肠系膜动脉平滑肌细胞中研究了缓激肽B1受体（B1R）抑制血小板源性生长因子（PDGF）刺激的增殖的机制。发现B1R激动剂des-Arg9-缓激肽（DABK）抑制PDGF介导的细胞周期蛋白E细胞周期蛋白依赖性激酶2（Cdk2）复合物的激活，并防止视网膜母细胞瘤蛋白过度磷酸化。 DABK不会抑制细胞周期蛋白E表达的上调，但会增加Cdk2抑制剂p27Kip1的表达以及p27Kip1与细胞周期蛋白E-Cdk2复合物的缔合。此外，DABK抑制了PDGF刺激的细胞周期蛋白D的表达，否则该表达会虹吸p27Kip1，而不会抑制细胞周期蛋白E-Cdk2。探索了DABK调节p27Kip1的信号传导机制。发现DABK刺激丝裂原激活的蛋白激酶激酶（MEK）和细胞外信号调节激酶（ERK）的活性，并延长PDGF对MEK和ERK的激活。 MEK抑制剂PD-98059和U-0126以及Src家族激酶抑制剂PP2对ERK激活的抑制作用完全阻断了DABK增加p27Kip1的作用，并部分逆转了DABK介导的对PDGF刺激的增殖的抑制作用。这些研究表明，B1R部分抑制了PDGF刺激的有丝分裂发生，部分原因是ERK的激活时间延长，导致p27Kip1表达增加。

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