p53 and tumor cell metabolism

p53与肿瘤细胞代谢

• 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
• 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

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）：该提案旨在定义肿瘤抑制p53在代谢调节中的作用，以及该功能在肿瘤发病机理中丧失的后果。 p53是人类癌症中最常见的基因的区别，其失活不仅对于形成较广泛的肿瘤的形成至关重要，而且对于它们的持续生存和增殖至关重要。能够理解p53抑制肿瘤发生的机制一直是癌症生物学的核心目的，该目标对治疗大量癌症类型具有重要意义。在p53引起的细胞反应中，新兴的证据表明，代谢调节和衰老对于抑制肿瘤至关重要。肿瘤细胞依靠重新编程的代谢来快速积累生物量并有效地最大程度地减少氧化损害。该提案的重点是麦芽酶和异氯酸盐脱氢酶（IDH）。这些是产生减少等效NADPH的主要酶，这对于生物合成和抗氧化剂防御至关重要。它们还与中央代谢中心的三羧酸周期（TCA循环）（TCA循环）有关，并且可能在HE代谢葡萄糖（尤其是谷氨酰胺）中起关键作用，这是肿瘤细胞的两种主要营养素。在我们的初步研究中，我们发现了p53和苹果酶之间以前意外的相互调节。 p53抑制了苹果酶的表达，而苹果酶的下调相互激活p53并调节p53激活的结果，从而导致衰老。此外，我们发现p53抑制了在未压力，尤其是压力的细胞中IDH1（一种主要的IDH同工型）的表达。这些发现表明，p53可能是NADPH代谢的中央前哨和主调节剂，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和苹果酶/IDH1之间的动态相互作用。我们的中心假设是，苹果酶和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剂反应，并有助于p53介导的肿瘤抑制。我们提出了三个特定目的：（1）确定p53和苹果酶在谷氨酰胺代谢中的功能； （2）阐明p53在调节IDH1和IDH1合作的代谢通量中的作用； （3）定义苹果酶在调节p53激活，抗氧化剂反应和衰老中的作用。拟议的研究将提高我们对代谢调节的关键方面的理解及其与P53介导的细胞命运决策的联系，并可能为将这些NADPH生成的酶定为癌症作为癌症的新疗法提供了理由。