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

描述(申请人提供)：丙酮酸激酶同工酶M2(PKM2)，它调节糖酵解的限速最后一步，在肿瘤发生中起重要作用。除了在细胞代谢中的作用已被充分研究外，PKM2还通过一种未知的机制促进细胞增殖。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，在那里PKM2与β-连环蛋白相互作用，并介导β-连环蛋白的反式激活。此外，PKM2使组蛋白H3和Bub3磷酸化，从而分别调节基因转录和细胞有丝分裂。我们假设，PKM2在控制基因表达和细胞周期进程的不同阶段具有重要作用，这在EGFR激活促进的肿瘤发展中起着重要作用。在特定的目标1中，我们将进一步阐明PKM2介导的基因转录的机制，并通过全基因组筛选鉴定PKM2调控的基因在癌细胞中的表达。在特定的目标2中，我们将阐明PKM2调节染色体分离的机制。在特定的目标3中，我们将确定PKM2调节的基因转录和染色体分离在EGFR促进的肿瘤发生中的作用。我们期望我们提出的研究将通过PKM2的非代谢功能为EGFR促进肿瘤发展提供重要且以前未被揭示的机制。基于我们的发现，针对PKM2调节的基因表达的治疗策略可能被开发出来，以加强目前基于EGFR的癌症治疗。

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.