This application seeks to define the regulation of the pentose phosphate pathway (PPP) by p53 family proteins, and the role of this metabolic pathway in tumorigenesis. Cancer cells are markedly different from normal cells in their metabolism. This metabolic reprogramming meets the demand of cancer cells for rapid production of macromolecules and effective detoxification of reactive oxygen species (ROS). Both macromolecule biosynthesis and ROS detoxification require NADPH (nicotinamide adenine dinucleotide phosphate, reduced), the intracellular reducing equivalent. NADPH is used in reductive biosynthetic processes and is also the ultimate reducing agent for various anti-oxidant systems. A major source of NADPH is the PPP, a glucose metabolic pathway that also provides cells with ribose for de novo nucleotide synthesis. Our preliminary results revealed that the PPP is regulated by both p53 and its structural homologue, TAp73. p53 is a preeminent tumor suppressor, and it is the most frequently mutated gene in human tumors. Nevertheless, how p53 prevents tumor formation is not well understood, and remains a central issue in tumor biology. In contrast to p53, TAp73 is rarely mutated in human tumors, and instead is often over-expressed. It is unclear whether TAp73 affords an advantage to tumor cells and if so, what the underlying mechanism may be. We have found that p53 directly binds to and inactivates glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. Through this inhibition, p53 regulates glucose metabolism, NADPH production, and biosynthesis. We have also shown that TAp73 supports tumor cell proliferation. Mechanistically, TAp73 enhances the expression of the G6PD gene, increases PPP flux, and directs glucose to the production of NADPH and ribose, for the synthesis of macromolecules and detoxification of ROS. Together, these findings shed important light on the roles of p53 and TAp73 in metabolism and proliferation. They also suggest that the PPP may be a focal point of regulation for cell proliferation and a valuable target for cancer therapy. We plan to further investigate the regulation of G6PD by p53 and TAp73, and role of the G6PD and the PPP in tumorigenesis. Our central hypothesis is that the regulation of G6PD by p53 and TAp73 is important for controlling biosynthesis and anti-oxidant response, and a hyperactive PPP due to p53 inactivation and TAp73 up-regulation contributes to tumorigenesis. We propose three specific aims: 1) Elucidate the mechanisms by which p53 and TAp73 regulate G6PD, 2) Define the activity of G6PD in oncogenic transformation, and 3) Determine the role of G6PD in the progression of cancer. The proposed studies will significantly improve our understanding of the functions of the p53 family proteins and the metabolic reprogramming in tumor cells. They will also likely provide a rationale for targeting p53- and TAp73-regulated metabolic enzymes as a new therapy for cancer.
The pentose phosphate pathway (PPP) supplies cells with metabolites critical for biosynthesis and anti-oxidant defense. The proposed research seeks to define the regulation of the PPP by the preeminent tumor suppressor p53 and the p53-related protein TAp73, and to determine the function of the PPP in tumorigenesis. It will substantially enhance our understanding of the functions of the p53 family proteins and the metabolic alterations in tumor cells, and will likely inform cancer therapy.
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