Role of p53 family proteins in glucose metabolism

p53家族蛋白在葡萄糖代谢中的作用

• 批准号: 9042843
• 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: 2014-05-06 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042843
• 关键词: Address; Anabolism; Antioxidants; Applications Grants; Biochemical; Bioenergetics; Biomass; Cancer Biology; Cells; Cellular Stress; Consumption; Defect; Drug Metabolic Detoxication; Enzymes; Exhibits; Family; Genes; Genetic Transcription; Genome Stability; Genomic Instability; Glucose; Glucosephosphate Dehydrogenase; Glycolysis; Growth; Health; Homologous Gene; Human; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mutate; Mutation; NADP; Neoplasm Metastasis; Nucleosides; Oncogenic; Oxidation-Reduction; Oxygen; Pathway interactions; Pentosephosphate Pathway; Process; Property; Protein Family; Protein Isoforms; Protein p53; Proteins; Reactive Oxygen Species; Regulation; Research; Research Proposals; Ribose; Role; TP53 gene; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Up-Regulation; Warburg Effect; aerobic glycolysis; cancer therapy; cancer type; cell growth; cell transformation; dimer; driving force; glucose metabolism; improved; monomer; mutant; neoplastic cell; novel therapeutics; nucleotide metabolism; overexpression; oxidative damage; programs; response; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): This proposal seeks to define the roles of the tumor suppressor p53, and its related protein TAp73, in glucose metabolism. p53 holds the distinction of being the most frequently mutated gene in human cancers, and its inactivation is essential for the survival and proliferation of tumor cells. The mechanism by which p53 and TAp73 influence tumorigenesis has been a central issue in cancer biology, one that has important implications in the treatment of a plethora of cancer types. In contrast to p53, TAp73 is rarely mutated in human tumors, and instead it is often over-expressed. It remains unclear whether TAp73 affords an advantage to tumor cells and if so, what the underlying mechanism is. Tumor cells rely on markedly re-programmed metabolism to rapidly accumulate biomass and effectively minimize oxidative damages. However, both the cause of the metabolic re-programming and its connection to tumor cell growth are still not well understood. During our preliminary studies, we found that p53 inhibits the pentose phosphate pathway (PPP), a major glucose metabolic pathway important for biosynthesis and anti-oxidant defense. Mechanistically, p53 inactivates glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, through a transcription-independent mechanism. We also showed that TAp73 supports the proliferation of tumor cells. As opposed to p53, TAp73 stimulates the expression of the G6PD genes, leading to an enhanced PPP flux. We plan to further investigate the mechanisms by which p53 and TAp73 regulate the PPP and coordinate the PPP with other metabolic pathways, and the role of the PPP in tumorigenesis. We propose three specific aims: 1) Elucidate the mechanism and consequence of p53-mediated inhibition of the PPP; 2) Define the role for TAp73 in regulating metabolism and maintaining genomic stability; and 3) Investigate the role of G6PD in tumor progression. The proposed studies will improve our understanding of key aspects of metabolic regulation and their link to p53 family proteins-mediated cell fate decision. They may also provide a rationale for targeting p53- and TAp73-regualted metabolic enzymes as a new therapy for cancer treatment.

描述（由申请人提供）：该提案旨在定义肿瘤抑制p53及其相关蛋白TAP73在葡萄糖代谢中的作用。 p53是人类癌症中最常见的基因的区别，其失活对于肿瘤细胞的存活和增殖至关重要。 p53和TAP73影响肿瘤发生的机制一直是癌症生物学的核心问题，该机制对多种癌症类型的治疗具有重要意义。与p53相比，TAP73在人类肿瘤中很少突变，而是经常表达过表达。尚不清楚TAP73是否对肿瘤细胞有优势，如果是，那么基础机制是什么。肿瘤细胞明显依赖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。但是，代谢重新编程的原因及其与肿瘤细胞生长的联系尚不清楚。在我们的初步研究中，我们发现p53抑制戊糖磷酸途径（PPP），这是一种对生物合成和抗氧化剂防御重要的主要葡萄糖代谢途径。从机械上讲，p53通过独立于转录的机制使PPP的速率限制酶灭活葡萄糖-6-磷酸脱氢酶（G6PD）。我们还表明，TAP73支持肿瘤细胞的增殖。与p53相反，TAP73刺激了G6PD基因的表达，从而导致PPP通量增强。我们计划进一步研究p53和TAP73调节PPP并与其他代谢途径协调的机制，以及PPP在肿瘤发生中的作用。我们提出了三个具体目标：1）阐明p53介导的PPP抑制的机制和结果； 2）定义TAP73在调节新陈代谢和维持基因组稳定性方面的作用； 3）研究G6PD在肿瘤进展中的作用。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家族蛋白介导的细胞命运决策的联系。他们还可以为靶向p53和TAP73登记的代谢酶作为癌症治疗的新疗法提供理由。