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.