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首页> 外文期刊>Molecular and Cellular Biology >Phosphoinositide 3-Kinase Activation in Late G1 Is Required for c-Myc Stabilization and S Phase Entry
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Phosphoinositide 3-Kinase Activation in Late G1 Is Required for c-Myc Stabilization and S Phase Entry

机译：c-Myc稳定和S期进入需要在G1晚期激活磷酸肌醇3-激酶

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摘要

Phosphoinositide 3-kinase (PI3K) is one of the early-signaling molecules induced by growth factor (GF) receptor stimulation that are necessary for cell growth and cell cycle entry. PI3K activation occurs at two distinct time points during G1 phase. The first peak is observed immediately following GF addition and the second in late G1, before S phase entry. This second activity peak is essential for transition from G1 to S phase; nonetheless, the mechanism by which this peak is induced and regulates S phase entry is poorly understood. Here, we show that activation of Ras and Tyr kinases is required for late-G1 PI3K activation. Inhibition of late-G1 PI3K activity results in low c-Myc and cyclin A expression, impaired Cdk2 activity, and reduced loading of MCM2 (minichromosome maintenance protein) onto chromatin. The primary consequence of inhibiting late-G1 PI3K was c-Myc destabilization, as conditional activation of c-Myc in advanced G1 as well as expression of a stable c-Myc mutant rescued all of these defects, restoring S phase entry. These results show that Tyr kinases and Ras cooperate to induce the second PI3K activity peak in G1, which mediates initiation of DNA synthesis by inducing c-Myc stabilization.
机译：磷酸肌醇3-激酶（PI3K）是由生长因子（GF）受体刺激诱导的早期信号分子之一，是细胞生长和进入细胞周期所必需的。 PI3K激活发生在G 1 阶段的两个不同时间点。加入GF后立即观察到第一个峰，进入S期之前在G 1 晚期观察到第二个峰。第二个活性峰是从G 1 过渡到S相所必需的;然而，对该峰的诱导和调节S相进入的机理了解甚少。在这里，我们表明，晚期G 1 PI3K激活需要激活Ras和Tyr激酶。晚期G 1 PI3K活性的抑制导致c-Myc和细胞周期蛋白A的表达降低，Cdk2活性受损以及MCM2（微染色体维持蛋白）在染色质上的负载减少。抑制晚期G 1 PI3K的主要结果是c-Myc失稳，高级G 1 中c-Myc的条件活化以及稳定c-表达的表达。 Myc突变体挽救了所有这些缺陷，恢复了S期进入。这些结果表明，Tyr激酶和Ras协同诱导G 1 中的第二个PI3K活性峰，该峰通过诱导c-Myc稳定来介导DNA合成的启动。

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