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首页> 外文期刊>Molecular and Cellular Biology >Hepatocyte Growth Factor Releases Mink Epithelial Cells from Transforming Growth Factor β1-Induced Growth Arrest by Restoring Cdk6 Expression and Cyclin E-Associated Cdk2 Activity
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Hepatocyte Growth Factor Releases Mink Epithelial Cells from Transforming Growth Factor β1-Induced Growth Arrest by Restoring Cdk6 Expression and Cyclin E-Associated Cdk2 Activity

机译：肝细胞生长因子通过恢复Cdk6表达和细胞周期蛋白E相关的Cdk2活性，从转化生长因子β1诱导的生长停滞中释放水貂上皮细胞。

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Transforming growth factor β (TGF-β) potently suppresses Mv1Lu mink epithelial cell growth, whereas hepatocyte growth factor (HGF) counteracts TGF-β-mediated growth inhibition and induces Mv1Lu cell proliferation (J. Taipale and J. Keski-Oja, J. Biol. Chem. 271:4342–4348, 1996). By addressing the cell cycle regulatory mechanisms involved in HGF-mediated release of Mv1Lu cells from TGF-β inhibition, we show that increased DNA replication is accompanied by phosphorylation of the retinoblastoma protein and alternative regulation of cyclin-Cdk-inhibitor complexes. While TGF-β treatment decreased the expression of Cdk6, this effect was counteracted by HGF, followed by partial restoration of cyclin D2-associated kinase activity. Notably, HGF failed to prevent TGF-β induction of p15 and its association with Cdk6. However, HGF reversed the TGF-β-mediated decrease in Cdk6-associated p27 and cyclin D2-associated Cdk6, suggesting that HGF modifies the TGF-β response at the level of G1 cyclin complex formation. Counteraction of TGF-β regulation of Cdk6 by HGF may in turn affect the association of p27 with Cdk2-cyclin E complexes. Though HGF did not differentially regulate the total levels of p27 in TGF-β-treated cells, p27 immunodepletion experiments suggested that upon treatment with both growth factors, less p27 is associated with Cdk2-cyclin E complexes, in parallel with restoration of the active form of Cdk2 and the associated kinase activity. The results demonstrate that HGF intercepts TGF-β cell cycle regulation at multiple points, affecting both G1and G1-S cyclin kinase activities.
机译：转化生长因子β（TGF-β）可以有效抑制Mv1Lu貂的上皮细胞生长，而肝细胞生长因子（HGF）则可以抵消TGF-β介导的生长抑制并诱导Mv1Lu细胞增殖（J.Taipale和J.Keski-Oja，J。生物化学杂志271：4342-4348，1996）。通过解决涉及HGF介导的Tv-β抑制作用释放Hv介导的Mv1Lu细胞释放的细胞周期调控机制，我们显示增加的DNA复制伴随着成视网膜细胞瘤蛋白的磷酸化和细胞周期蛋白-Cdk-抑制剂复合物的替代调控。尽管TGF-β处理降低了Cdk6的表达，但这种作用被HGF抵消，随后部分恢复了细胞周期蛋白D2相关的激酶活性。值得注意的是，HGF未能阻止TGF-β诱导p15及其与Cdk6的结合。然而，HGF逆转了Tdg-β介导的Cdk6相关的p27和细胞周期蛋白D2相关的Cdk6的减少，表明HGF在G 1 细胞周期蛋白复合物形成水平上修饰了TGF-β反应。 HGF对Cdk6的TGF-β调节作用可能反过来影响p27与Cdk2-cyclin E复合物的缔合。尽管HGF不能差异调节TGF-β处理的细胞中p27的总水平，但p27免疫耗竭实验表明，在用两种生长因子处理后，与Cdk2-cyclin E复合物相关的p27较少，同时活性形式也得以恢复Cdk2和相关激酶的活性结果表明，HGF在多个点上都阻断了TGF-β的细胞周期调控，影响了G 1 和G 1 -S细胞周期蛋白激酶的活性。

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