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INACTIVATION OF P27(KIP1) BY THE VIRAL E1A ONCOPROTEIN IN TGF-BETA-TREATED CELLS

机译:病毒E1A癌蛋白在TGF-BETA处理的细胞中对P27(KIP1)的灭活

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THE adenovirus oncoprotein E1A and the simian virus SV40 large T antigen can both reverse the strong growth-inhibitory effect of transforming growth factor(TGF)-beta on mink lung epithelial cells(1,2): exposure of TGF-beta causes these cells to arrest late in the G1 phase of the cell cycle (ref. 3). This arrest correlates with an increase in expression of the protein p15(Ink4B) (ref. 4), inactivation of the cyclin E/A-cdk2 complex by the inhibitory protein p27(Kip1) (refs 5-7), and with the accumulation of unphosphorylated retinoblastoma protein(8). The rescue by E1A of cells from TGF-beta arrest is partly independent of its binding to retinoblastoma protein(1). Here we show that E1A directly affects the cyclin-dependent kinase inhibitor p27(Kip1) in TGF-beta-treated cells by binding to it and blocking its inhibitory effect, thereby restoring the activity of the cyclin-cdk2 kinase complex. In this way, E1A can overcome the effect of TGF-beta and modulate the cell cycle. To our knowledge, E1A provides the first example of a viral oncoprotein that can disable a cellular protein whose function is to inhibit the activity of cyclin-dependent kinases. [References: 26]
机译:腺病毒癌蛋白E1A和猿猴病毒SV40大T抗原均可逆转转化生长因子(TGF)-β对水貂肺上皮细胞的强生长抑制作用(1,2):TGF-β暴露会导致这些细胞在细胞周期的G1期晚期停止(参考3)。该停滞与蛋白p15(Ink4B)表达的增加(参考文献4),抑制蛋白p27(Kip1)抑制细胞周期蛋白E / A-cdk2复合物(参考文献5-7)和积累有关磷酸化视网膜母细胞瘤蛋白的表达(8)。 E1A对TGF-β逮捕的细胞救助部分独立于其与成视网膜细胞瘤蛋白的结合(1)。在这里,我们显示E1A通过与TGF-β结合并阻断其抑制作用而直接影响TGF-β处理的细胞中的细胞周期蛋白依赖性激酶抑制剂p27(Kip1),从而恢复了细胞周期蛋白-cdk2激酶复合物的活性。通过这种方式,E1A可以克服TGF-β的作用并调节细胞周期。据我们所知,E1A提供了病毒癌蛋白的第一个例子,它可以使细胞蛋白失活,而该细胞蛋白的功能是抑制细胞周期蛋白依赖性激酶的活性。 [参考:26]

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