The Mechanisms of PKM2-Regulated Gene Expression in Tumor Development.

肿瘤发展中 PKM2 调节基因表达的机制。

基本信息

批准号：
9230820
负责人：
ZHIMIN LU
金额：
$ 33.2万
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：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9230820
关键词：
Acetylation Adenosine Triphosphate Binding Brain CCND1 gene CD2 gene Cancer Patient Cell Cycle Progression Cell Nucleus Cell Proliferation Cells Cellular Metabolic Process ChIP-seq Chromosome Segregation Chromosome abnormality Chromosomes Cultured Tumor Cells Cyclic AMP-Dependent Protein Kinases Cyclin D1 DNA Data Development Differentiated Gene EGF gene Enzymes Epidermal Growth Factor Receptor G1 Phase Gene Chips Gene Expression Gene Expression Profile Genes Genetic Transcription Glioma Glycolysis Goals Growth and Development function Histone Acetylation Histone H3 Human Isoenzymes Kinetochores Lead Lysine Malignant Neoplasms Malignant neoplasm of lung Mediating Microtubules Mitosis Molecular Profiling Mus Nature Nuclear Translocation Oxygen Phase Phase Transition Phosphorylation Phosphotransferases Play Production Prognostic Marker Promoter Regions Protein Isoforms Protein Kinase Proteins Public Health Publications Publishing Pyruvate Kinase Recruitment Activity Regulation Research Role Specimen Therapeutic Threonine Transactivation Tyrosine Warburg Effect aerobic glycolysis base c-myc Genes cancer biomarkers cancer cell cancer genome cancer therapy cell growth clinically relevant clinically significant cyclin C daughter cell genome-wide analysis glucose uptake histone acetyltransferase innovation migration neoplastic cell novel outcome forecast overexpression public health relevance tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Pyruvate kinase isozyme type M2 (PKM2), which regulates the rate-limiting final step of glycolysis, is instrumental in tumorigenesis. In additionto its well-studied role in cell metabolism, PKM2 promotes cell proliferation though an unknown mechanism. Our recent published and preliminary data show that activation of EGFR results in PKM2 translocation into the nucleus, where PKM2 interacts with �-catenin and mediates �-catenin-transactivation. In addition, PKM2 phosphorylates histone H3 and Bub3, subsequently regulating gene transcription and cell mitosis, respectively. We hypothesize that PKM2 has an essential role in controlling gene expression and different phases of cell cycle progression, which is instrumental in EGFR activation-promoted tumor development. In Specific Aim 1, we will further elucidate the mechanisms underlying PKM2-mediated gene transcription and identify PKM2-regulated expression of genes in cancer cells by genome-wide screening. In Specific Aim 2, we will elucidate the mechanisms underlying PKM2-regulated chromosome segregation. In Specific Aim 3, we will determine the role of PKM2- regulated gene transcription and chromosome segregation in EGFR-promoted tumorigenesis. We expect that our proposed research will provide important and previously unrevealed mechanisms of EGFR-promoted tumor development via nonmetabolic functions of PKM2. Building on our findings, therapeutic strategies targeting PKM2-regulated gene expression may be developed to enhance current EGFR-based cancer therapies.

描述（由申请人提供）：M2型丙酮酸激酶同工酶（PKM2）调节糖酵解的限速最终步骤，在肿瘤发生中发挥重要作用。除了其在细胞代谢中的作用得到充分研究外，PKM2还通过促进细胞增殖。我们最近发表的初步数据表明，EGFR 的激活导致 PKM2 易位到细胞核中，其中 PKM2 与β-连环蛋白相互作用。此外，PKM2 磷酸化组蛋白 H3 和 Bub3，随后分别调节基因转录和细胞有丝分裂，我们认为 PKM2 在控制基因表达和细胞周期进展的不同阶段中具有重要作用。在 EGFR 激活促进肿瘤发展中发挥重要作用在具体目标 1 中，我们将进一步阐明 PKM2 介导的转录基因的机制并鉴定 PKM2 调节的表达。在特定目标 2 中，我们将阐明 PKM2 调节的染色体分离的机制。在特定目标 3 中，我们将确定 PKM2 调节的基因转录和染色体分离在 EGFR 中的作用。我们期望我们提出的研究将通过 PKM2 的非代谢功能提供先前未揭示的重要机制。可以开发针对 PKM2 调节基因表达的策略来增强当前基于 EGFR 的癌症疗法。