Role of p53 family proteins in glucose metabolism

描述（由申请人提供）：本提案旨在定义肿瘤抑制因子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突变基因，它的失活对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中的一个核心问题，在治疗多种癌症类型中具有重要意义。与p53相反，TAp73在人类肿瘤中很少发生突变，而是经常过度表达。目前尚不清楚TAp73是否对肿瘤细胞有优势，如果有，其潜在机制是什么。肿瘤细胞依靠明显的重编程代谢来快速积累生物量并有效地减少氧化损伤。然而，代谢重编程的原因及其与肿瘤细胞生长的关系仍不清楚。在我们的初步研究中，我们发现p53抑制戊糖磷酸途径（PPP），这是一种重要的葡萄糖代谢途径，对生物合成和抗氧化防御很重要。从机制上讲，p53通过转录不依赖的机制使PPP的限速酶葡萄糖-6-磷酸脱氢酶（G6PD）失活。我们还发现TAp73支持肿瘤细胞的增殖。与p53相反，TAp73刺激G6PD基因的表达，导致PPP通量增强。我们计划进一步研究p53和TAp73调控PPP、协调PPP与其他代谢途径的机制，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抑制的机制和后果；2)明确TAp73在调节代谢和维持基因组稳定性中的作用；3)探讨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及其与p53家族蛋白介导的细胞命运决定的联系的理解。它们也可能为靶向p53-和tap73调节的代谢酶作为癌症治疗的新疗法提供理论依据。

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.