Control of Nucleotide Metabolism Enables Mutant p53's Oncogenic Gain-of-Function Activity

Abstract

Since its discovery as an oncoprotein in 1979, investigation into p53's many identities has completed a full circle and today it is inarguably the most extensively studied tumor suppressor (wild-type p53 form or WTp53) and oncogene (mutant p53 form or mtp53) in cancer research. After the p53 protein was declared "Molecule of the Year" by Science in 1993, the p53 field exploded and a plethora of excellent reviews is now available on every aspect of p53 genetics and functional repertoire in a cell. Nevertheless, new functions of p53 continue to emerge. Here, we discuss a novel mechanism that contributes to mtp53's Gain of Functions GOF (gain-of-function) activities and involves the upregulation of both nucleotide de novo synthesis and nucleoside salvage pathways.

Keywords: ETS2; GOFs; nucleotide metabolism; p53.

Figure 1

An overview of nucleotide synthesis. PRPP = 5-phospho ribosyl pyro phosphate; ATASE = amidophosphoribosyltransferase; IMP = inosine mono phosphate; AMP = adenosine mono phosphate; GMP = guanosine mono phosphate; CMP = cytidine mono phosphate; GMPS = guanosine mono phosphate synthetase; UMP = uridine mono phosphate; TS = thymidine synthetase; dATP = deoxyadenosine tri phosphate; dGTP = deoxyguanosine tri phosphate; dCTP = deoxycytosine tri phosphate; dTMP = deoxythymidine mono phosphate; APRT = adenine phosphoribosyl transferases; HGPRT = hypoxanthine-guanine phosphoribosyl transferases; dCK = deoxycytidine kinase; dGK = deoxyguanosine kinase. The dotted line represents the multiple steps.

Figure 2

Schematic showing the mechanisms of cancer cells metastasis in brain. Adapted and modified from Chen et al. [90].