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

Valentina Schmidt,Rachana Nagar,Luis Martinez

doi:10.3390/ijms18122759

Valentina Schmidt, Rachana Nagar + Show 1 more

Open Access

https://doi.org/10.3390/ijms18122759

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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.

Highlights

TP53, a gene which is located on chromosome 17p13.1 and encodes p53 protein, is more frequently mutated in various human tumors than any other gene in the genome [1]
We showed that mtp53/ETS2 complex upregulates the expression of 5 -tyrosyl DNA phosphodiesterase TDP2, which is involved in the repair of DNA damage and promotes resistance to a chemotherapeutic agent etoposide [38]
Emerging evidence presented in this review identifies the control of nucleotide pools as an important component of mtp53 GOF activities, which validates further exploration

Summary

Mutant p53’s Oncogenic Gain-of-Function

TP53, a gene which is located on chromosome 17p13.1 and encodes p53 protein, is more frequently mutated in various human tumors than any other gene in the genome [1]. A sequence-specific transcription factor, wild-type p53 (WTp53), has the distinction of being the first tumor suppressor protein identified [2] It guards the organism by eliminating damaged cells mainly through the control of signaling pathways regulating DNA repair, cell-cycle progression, senescence, and apoptosis [3]. The confirmed mechanisms of mtp GOF include the inhibition of p63- and p73-mediated transcription of WTp53 target genes through a physical interaction with p63 and p73 [18,19]; activation of oncogenic target genes through a direct interaction with their transcription factors; regulation of specific gene promoter transcription activities through a structure-dependent DNA binding; and a physical interaction with cytoplasmic proteins other than transcription factors [6,12]. This emerging evidence suggests a novel ETS2-dependent mechanism for diverse mtp53’s GOF activities and warrants further investigation [40]

Nucleotide Metabolism and Its Regulation

Control of Nucleotide Metabolism by Mtp53

Conclusions