Deciphering the role of Cdc25A in cancer metabolism.

 描述(申请人提供)：CDC25A是细胞周期进程中的一种辅助蛋白磷酸酶，在许多类型的人类癌症中过度表达。然而，CDC25A在肿瘤代谢中的作用尚不清楚，尽管它在CDK去磷酸化调节中的作用已经得到证实，但CDC25A可能含有其他重要的细胞底物。我们发现，EGF刺激诱导胞浆中PKM2的磷酸化，这对PKM2的核转位是必不可少的。在细胞核中，PKM2通过与CDc25A相互作用而去磷酸化，这是EGF诱导的？连环蛋白反式激活所必需的。我们假设，CDC25A通过使核PKM2去磷酸化来调节癌症代谢和肿瘤进展。为了验证这一假说，我们将追求三个特定的目标：(1)进一步阐明依赖于CDc25A的PKM2去磷酸化和随后激活？连环蛋白的机制；(2)确定依赖于CDc25A的PKM2去磷酸化在Warburg效应、肿瘤细胞增殖和脑肿瘤发生中的作用；以及(3)确定依赖于CDc25A的PKM2去磷酸化在人脑胶质瘤中的临床意义。这项拟议的研究意义重大，因为它可能导致通过阻断CDC25A的功能来中断癌症代谢的药物方法；这反过来将提高人类癌症治疗的效率。

 DESCRIPTION (provided by applicant): Cdc25A is an instrumental protein phosphatase in cell cycle progression that is overexpressed in many types of human cancer. However, the role of Cdc25A in cancer metabolism is unclear, and although its role in the regulation of Cdk dephosphorylation is well established, Cdc25A may contain other important cellular substrates. We revealed that EGF stimulation induces PKM2 phosphorylation in the cytosol, which is essential for the nuclear translocation of PKM2. In the nucleus, PKM2 is dephosphorylated by interacting with Cdc25A, which is required for EGF-induced ß-catenin transactivation. We hypothesize that Cdc25A regulates cancer metabolism and tumor progression by dephosphorylating nuclear PKM2. To test this hypothesis, we will pursue three specific aims: (1) To further elucidate the mechanisms underlying Cdc25A-dependent PKM2 dephosphorylation and the subsequent activation of ß-catenin; (2) To determine the role of Cdc25A-dependent PKM2 dephosphorylation in the Warburg effect, tumor cell proliferation, and brain tumorigenesis; and (3) To determine the clinical significance of Cdc25A-dependent PKM2 dephosphorylation in human glioma. The proposed research is significant because it could lead to pharmaceutical approaches to interrupt cancer metabolism by blocking the function of Cdc25A; this would, in turn, improve the efficacy of human cancer treatment.