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首页> 外文期刊>Molecular and Cellular Biology >The viral oncoprotein E1A blocks transforming growth factor beta-mediated induction of p21/WAF1/Cip1 and p15/INK4B.
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The viral oncoprotein E1A blocks transforming growth factor beta-mediated induction of p21/WAF1/Cip1 and p15/INK4B.

机译：病毒癌蛋白E1A阻断转化生长因子β介导的p21 / WAF1 / Cip1和p15 / INK4B的诱导。

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The adenovirus early gene product E1A is a potent stimulator of cellular proliferation, which when overexpressed can overcome the growth-inhibitory effects of the polypeptide hormone transforming growth factor beta (TGF-beta). The ability of TGF-beta to arrest cell growth in G1 correlates with the transcriptional induction of the cyclin-dependent kinase inhibitors, p15/INK4B and p21/WAF1/Cip1; an inhibition of the G1 cyclin-Cdk complexes; and a maintenance of the retinoblastoma susceptibility gene product, Rb, in a hypophosphorylated state. The ability of E1A to overcome TGF-beta-mediated growth inhibition derives, in part, from its ability to sequester Rb and Rb family members. We report here that E1A also acts upstream of Rb by blocking the TGF-beta-mediated induction of p15 and p21. Consistent with these findings, E1A expression also blocks the ability of TGF-beta to inhibit Cdk2 kinase activity, as well as its ability to hold Rb in a hypophosphorylated state. The effect of E1A on the induction of p15 and p21 is independent of E1A's Rb binding activity. The E1A-mediated decrease in p15 levels is primarily the result of a block at the level of transcriptional activation by TGF-beta. This effect is dependent on E1A's ability to bind p300, one of E1A's target proteins. Thus, the ability of E1A to affect p15 and p21 expression represents an additional possible mechanism by which E1A can circumvent the negative regulation of cell cycle progression.
机译：腺病毒早期基因产物E1A是细胞增殖的有效刺激剂，当它过度表达时，可以克服多肽激素转化生长因子β（TGF-β）的生长抑制作用。 TGF-β阻止G1细胞生长的能力与细胞周期蛋白依赖性激酶抑制剂p15 / INK4B和p21 / WAF1 / Cip1的转录诱导有关。抑制G1细胞周期蛋白-Cdk复合物;并维持视网膜母细胞瘤易感基因产物Rb处于低磷酸化状态。 E1A克服TGF-β介导的生长抑制的能力部分源于其螯合Rb和Rb家族成员的能力。我们在这里报告，E1A还通过阻止TGF-β介导的p15和p21的诱导而在Rb的上游起作用。与这些发现一致，E1A表达还阻断了TGF-β抑制Cdk2激酶活性的能力，以及将Rb保持在低磷酸化状态的能力。 E1A对p15和p21的诱导作用与E1A的Rb结合活性无关。 E1A介导的p15水平降低主要是由于TGF-beta转录激活水平受阻所致。这种作用取决于E1A结合p300（E1A的靶蛋白之一）的能力。因此，E1A影响p15和p21表达的能力代表了另一种可能的机制，通过该机制E1A可以规避细胞周期进程的负调控。

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