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Deciphering the role of Cdc25A in cancer metabolism.

解读 Cdc25A 在癌症代谢中的作用。

基本信息

批准号：
9272014
负责人：
ZHIMIN LU
金额：
$ 35万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2018-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272014
关键词：
Binding Brain CD2 gene Cancer Patient Cell Cycle Cell Cycle Progression Cell Nucleus Cell Proliferation Cellular Metabolic Process Cyclin D1 Cyclin-Dependent Kinases Cytosol Data Development EGF gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Extracellular Signal Regulated Kinases Genetic Transcription Glioma Glycolysis Goals Histone H3 Human Interruption Lead Malignant Neoplasms Mediating Mitogen-Activated Protein Kinases Mutation Nuclear Nuclear Translocation Patients Pharmacologic Substance Phosphoric Monoester Hydrolases Phosphorylation Play Process Prognostic Marker Protein Dephosphorylation Protein Isoforms Protein phosphatase Public Health Pyruvate Kinase Regulation Reporting Research Resistance Role SRC gene Specimen Testing Transactivation Treatment Efficacy Tyrosine Tyrosine Phosphorylation Warburg Effect Xenograft Model base beta catenin biomarker identification c-myc Genes cancer therapy clinical efficacy clinically significant cyclin C improved innovation neoplastic cell novel outcome forecast overexpression public health relevance therapeutic development tumor tumor metabolism tumor progression tumorigenesis

项目摘要

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.

描述（由申请人提供）：Cdc25A 是细胞周期进程中的一种重要蛋白磷酸酶，在许多类型的人类癌症中过度表达。然而，Cdc25A 在癌症代谢中的作用尚不清楚，尽管其在调节 Cdk 去磷酸化中的作用已得到充分证实，但 Cdc25A 可能含有其他重要的细胞底物。我们发现 EGF 刺激会诱导细胞质中的 PKM2 磷酸化，这对于 PKM2 的核转位至关重要。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 ß-连环蛋白反式激活所必需的。我们假设 Cdc25A 通过去磷酸化核 PKM2 来调节癌症代谢和肿瘤进展。为了检验这一假设，我们将追求三个具体目标：（1）进一步阐明Cdc25A依赖性PKM2去磷酸化和随后β-连环蛋白激活的机制； (2) 确定Cdc25A依赖性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； (3) 确定人胶质瘤中 Cdc25A 依赖性 PKM2 去磷酸化的临床意义。拟议的研究意义重大，因为它可能导致通过阻断 Cdc25A 功能来中断癌症代谢的药物方法；这反过来又会提高人类癌症治疗的功效。