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首页> 外文期刊>Journal of cellular biochemistry. >IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry.
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IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry.

机译:IGF-1在促进细胞周期S期进入中诱导Pin1表达。

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摘要

Insulin-like growth factor I (IGF-1) is a well-established mitogen to many different cell types and is implicated in progression of a number of human cancers, notably breast cancer. The prolyl isomerase Pin1 plays an important role in cell cycle regulation through its specific interaction with proteins that are phosphorylated at Ser/Thr-Pro motifs. Pin1 knockout mice appear to have relatively normal development yet the Pin1(-/-)mouse embryo fibroblast (MEF) cells are defective in re-entering cell cycle in response to serum stimulation after G0 arrest. Here, we report that Pin1(-/-) MEF cells display a delayed cell cycle S-phase entry in response to IGF stimulation and that IGF-1 induces Pin1 protein expression which correlates with the induction of cyclin D1 and RB phosphorylation in human breast cancer cells. The induction of Pin1 by IGF-1 is mediated via the phosphatidylinositol 3-kinase as well as the MAP kinase pathways. Treatment of PI3K inhibitor LY294002 and the MAP kinase inhibitor PD098059, but not p38 inhibitor SB203580, effectively blocks IGF-1-induced upregulation of Pin1, cyclin D1 and RB phosphorylation. Furthermore, we found that Cyclin D1 expression and RB phosphorylation are dramatically decreased in Pin1(-/-) MEF cells. Reintroducing a recombinant adenovirus encoding Pin1 into Pin1(-/-) MEF cells restores the expression of cyclin D1 and RB phosphorylation. Thus, these data suggest that the mitogenic function of IGF-1 is at least partially linked to the induction of Pin1, which in turn stimulates cyclin D1 expression and RB phosphorylation, therefore contributing to G0/G1-S transition.
机译:胰岛素样生长因子I(IGF-1)是许多不同细胞类型中公认的促分裂原,与许多人类癌症(尤其是乳腺癌)的进展有关。脯氨酰异构酶Pin1通过与Ser / Thr-Pro基序磷酸化的蛋白质发生特异性相互作用,在细胞周期调控中发挥重要作用。 Pin1基因敲除小鼠似乎具有相对正常的发展,但Pin1(-/-)小鼠胚胎成纤维细胞(MEF)细胞在重新进入细胞周期方面存在缺陷,以响应G0逮捕后的血清刺激。在这里,我们报道Pin1(-/-)MEF细胞响应IGF刺激显示延迟的细胞周期S期进入和IGF-1诱导Pin1蛋白表达,其与人乳腺细胞周期蛋白D1和RB磷酸化的诱导有关癌细胞。 IGF-1对Pin1的诱导是通过磷脂酰肌醇3激酶以及MAP激酶途径介导的。 PI3K抑制剂LY294002和MAP激酶抑制剂PD098059而非p38抑制剂SB203580的治疗有效地阻断了IGF-1诱导的Pin1,cyclin D1和RB磷酸化的上调。此外,我们发现Pin1(-/-)MEF细胞中Cyclin D1表达和RB磷酸化显着降低。重新将编码Pin1的重组腺病毒引入Pin1(-/-)MEF细胞可恢复细胞周期蛋白D1和RB磷酸化的表达。因此,这些数据表明IGF-1的促有丝分裂功能至少部分与Pin1的诱导有关,Pin1的诱导又刺激细胞周期蛋白D1的表达和RB磷酸化,从而促进了G0 / G1-S的转变。

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