Role of Malic Enzymes in Tumorigenesis

描述(申请人提供)：这项建议旨在描述肿瘤抑制基因P53在细胞代谢中的作用，以及在肿瘤发病机制中失去这一功能的后果。抑癌基因P53是人类肿瘤中最常见的突变基因。P53诱导多种抗增殖过程以响应促肿瘤压力，最近的证据表明P53介导的代谢调节在肿瘤抑制中起着关键作用。然而，p53控制的代谢基因对肿瘤的发展至关重要，目前仍不清楚。在我们的初步研究中，我们发现P53抑制苹果酸酶1(ME1)和苹果酸酶2(ME2)基因的表达。这些酶催化苹果酸--一种三羧酸循环(TCA循环)的中间体--的脱羧基 常见的TCA循环碳源丙酮酸，因此可能在将TCA通量与细胞对能量的需求相匹配、减少当量和生物合成前体方面发挥调节作用。我们假设，p53对MES的抑制对于控制细胞增殖所需的代谢活动是重要的，而由于p53失活而导致的这一调控的丧失有助于肿瘤的发生。我们提出了三个具体目标来确定MES在新陈代谢、抗氧化反应和肿瘤发生中的作用。建议的研究将有助于更好地理解新陈代谢和P53介导的肿瘤抑制之间的联系。它们还将揭示对肿瘤发生至关重要的代谢变化，并可能确定肿瘤治疗的有价值的靶点。

DESCRIPTION (provided by applicant): This proposal aims to characterize the role of the tumor suppressor p53 in cellular metabolism and the consequence of losing this function in tumor pathogenesis. The tumor suppressor p53 is the most frequently mutated gene in human tumors. p53 induces various anti-proliferative processes in response to tumor- promoting stresses, and recent evidence indicated a critical role for p53-mediated metabolic regulation in tumor suppression. However, the p53-controlled metabolic genes that are important for tumor development are still unclear. In our preliminary studies, we found that p53 suppresses the expression of malic enzyme 1 (ME1) and malic enzyme 2 (ME2) genes. These enzymes catalyze the decarboxylation of malate - a tricarboxylic acid cycle (TCA cycle) intermediate - into the common TCA cycle carbon source pyruvate, and thus may have a regulatory role in matching TCA flux to cellular demand for energy, reducing equivalents, and biosynthetic precursors. We hypothesize that suppression of MEs by p53 is important for controlling metabolic activities required for cell proliferation, and that loss of this regulation due to p53 inactivation contributes to tumorigenesis. We propose three specific aims to determine the functions of MEs in metabolism, anti-oxidant response, and tumorigenesis, respectively. The proposed studies will lead to a better understanding of the links between metabolism and p53-mediated tumor suppression. They will also reveal metabolic alterations important for tumorigenesis and may identify valuable targets for tumor therapy.