p53 and tumor cell metabolism

p53与肿瘤细胞代谢

基本信息

批准号：
9307557
负责人：
Xiaolu Yang
金额：
$ 33.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307557
关键词：
Anabolism Antioxidants Biomass CELSR1 gene Cancer Biology Cells Cellular Stress Citric Acid Cycle Down-Regulation Drug Metabolic Detoxication Drug Targeting Enzymes Feedback Genes Glutamine Human Isocitrate Dehydrogenase Link Maintenance Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolic stress Metabolism Mutate Mutation NADP Nature Nutrient Outcome Oxidation-Reduction Oxidative Stress Pathogenesis Pathway interactions Play Production Proliferating Protein Isoforms Protein p53 Proteins Reactive Oxygen Species Regulation Research Research Proposals Role Sentinel TP53 gene Testing Therapeutic Tissues Tumor Suppression cancer therapy cancer type feeding glucose metabolism improved loss of function macromolecule malic enzyme neoplastic cell novel therapeutics oxidative damage protein protein interaction public health relevance response senescence tumor tumor growth tumor metabolism tumorigenesis virtual

项目摘要

DESCRIPTION (provided by applicant): This proposal aims to define the role of the tumor suppressor p53 in the regulation of metabolism, as well as the consequences of the loss of this function in tumor pathogenesis. p53 holds the distinction of being the most frequently mutated gene in human cancers, and its inactivation is essential not only for the formation of a remarkably wide range of tumors, but also for their continued survival and proliferation. Being able to understand the mechanism by which p53 suppresses tumorigenesis has been a central objective in cancer biology, one which has important implications in the treatment of a plethora of cancer types. Among the cellular response elicited by p53, emerging evidence has indicated that metabolic modulation and senescence are crucial for tumor suppression. Tumor cells rely on re-programmed metabolism to rapidly accumulate biomass and to effectively minimize oxidative damages. This proposal focuses on malic enzyme and isocitrate dehydrogenase (IDH). These are major enzymes that generate the reducing equivalent NADPH, which is essential for biosynthesis and anti-oxidant defense. They are also associated with the tricarboxylic acid cycle (TCA cycle), the central metabolic hub, and likely play critical roles in he metabolism of glucose and especially glutamine, two major nutrients for tumor cells. In our preliminary studies, we found previously unanticipated mutual regulation between p53 and malic enzymes. p53 suppresses the expression of malic enzymes, while down-regulation of malic enzymes reciprocally activates p53 and modulates the outcome of p53 activation, leading to senescence. Furthermore, we found that p53 suppresses the expression of IDH1, a major IDH isoform, in unstressed and especially stressed cells. These findings suggest that p53 may function as both a central sentinel and a master regulator of NADPH metabolism, linking the metabolic state of the cell with the cell fate decision. We plan to investigate the dynamic interplays between p53 and malic enzymes/IDH1. Our central hypothesis is that mutual regulation between malic enzymes and p53, as well as the suppression of IDH1 by p53, modulates biosynthesis and anti-oxidant response, and contributes to p53-mediated tumor suppression. We propose three specific aims: (1) Determine the functions of p53 and malic enzymes in glutamine metabolism; (2) Elucidate the role of p53 in regulating IDH1 and IDH1-assoicated metabolic fluxes; and (3) Define the role of malic enzymes in regulating p53 activation, anti-oxidant response, and senescence. The proposed studies will improve our understanding of key aspects of metabolic regulation and their link to p53-mediated cell fate decision, and may provide a rationale for targeting these NADPH-generating enzymes as a new therapy for cancer.

描述（由申请人提供）：该提案旨在明确肿瘤抑制因子p53在代谢调节中的作用，以及该功能丧失在肿瘤发病机制中的后果。 p53 是人类癌症中最常见的突变基因，其失活不仅对于多种肿瘤的形成至关重要，而且对于肿瘤的持续生存和增殖也至关重要。能够了解 p53 抑制肿瘤发生的机制一直是癌症生物学的核心目标，这对于治疗多种癌症类型具有重要意义。在 p53 引发的细胞反应中，新出现的证据表明代谢调节和衰老对于肿瘤抑制至关重要。肿瘤细胞依靠重新编程的新陈代谢来快速积累生物量并有效地减少氧化损伤。该提案重点关注苹果酸酶和异柠檬酸脱氢酶（IDH）。这些是产生还原当量 NADPH 的主要酶，这对于生物合成和抗氧化防御至关重要。它们还与中央代谢枢纽三羧酸循环（TCA 循环）相关，并且可能在葡萄糖（尤其是肿瘤细胞的两种主要营养物质谷氨酰胺）的代谢中发挥关键作用。在我们的初步研究中，我们发现了 p53 和苹果酸酶之间先前未预料到的相互调节。 p53 抑制苹果酸酶的表达，而苹果酸酶的下调会反过来激活 p53 并调节 p53 激活的结果，从而导致衰老。此外，我们发现 p53 在未受应激和特别受应激的细胞中抑制 IDH1（一种主要的 IDH 亚型）的表达。这些发现表明，p53 可能既是 NADPH 代谢的中枢哨兵，又是 NADPH 代谢的主调节因子，将细胞的代谢状态与细胞命运决定联系起来。我们计划研究 p53 和苹果酸酶/IDH1 之间的动态相互作用。我们的中心假设是苹果酸酶和 p53 之间的相互调节以及 p53 对 IDH1 的抑制，调节生物合成和抗氧化反应，并有助于 p53 介导的肿瘤抑制。我们提出了三个具体目标：（1）确定p53和苹果酸酶在谷氨酰胺代谢中的功能； (2)阐明p53在调节IDH1和IDH1相关代谢通量中的作用； (3) 定义苹果酸酶在调节 p53 激活、抗氧化反应和衰老中的作用。拟议的研究将提高我们对代谢调节关键方面及其与 p53 介导的细胞命运决定的联系的理解，并可能为将这些 NADPH 生成酶作为癌症的新疗法提供理论依据。