Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities

Madhusudhan Kollareddy, Elizabeth Dimitrova, Krishna C. Vallabhaneni, Adriano Chan, Thuc Le, Krishna M. Chauhan, Zunamys I. Carrero, Gopalakrishnan Ramakrishnan, Kounosuke Watabe, Ygal Haupt, Sue Haupt, Radhika Pochampally, Gerard R. Boss, Damian G. Romero, Caius G. Radu and Luis A. Martinez ()
Additional contact information
Madhusudhan Kollareddy: University of Mississippi Medical Center
Elizabeth Dimitrova: University of California
Krishna C. Vallabhaneni: University of Mississippi Medical Center
Adriano Chan: University of California, San Diego
Thuc Le: University of California
Krishna M. Chauhan: University of Mississippi Medical Center
Zunamys I. Carrero: University of Mississippi Medical Center
Gopalakrishnan Ramakrishnan: University of Mississippi Medical Center
Kounosuke Watabe: University of Mississippi Medical Center
Ygal Haupt: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Locked Bag, East Melbourne, Victoria 3002, Australia
Sue Haupt: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Locked Bag, East Melbourne, Victoria 3002, Australia
Radhika Pochampally: University of Mississippi Medical Center
Gerard R. Boss: University of California, San Diego
Damian G. Romero: University of Mississippi Medical Center
Caius G. Radu: University of California
Luis A. Martinez: University of Mississippi Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Mutant p53 (mtp53) is an oncogene that drives cancer cell proliferation. Here we report that mtp53 associates with the promoters of numerous nucleotide metabolism genes (NMG). Mtp53 knockdown reduces NMG expression and substantially depletes nucleotide pools, which attenuates GTP-dependent protein activity and cell invasion. Addition of exogenous guanosine or GTP restores the invasiveness of mtp53 knockdown cells, suggesting that mtp53 promotes invasion by increasing GTP. In addition, mtp53 creates a dependency on the nucleoside salvage pathway enzyme deoxycytidine kinase for the maintenance of a proper balance in dNTP pools required for proliferation. These data indicate that mtp53-harbouring cells have acquired a synthetic sick or lethal phenotype relationship with the nucleoside salvage pathway. Finally, elevated expression of NMG correlates with mutant p53 status and poor prognosis in breast cancer patients. Thus, mtp53’s control of nucleotide biosynthesis has both a driving and sustaining role in cancer development.

Date: 2015
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DOI: 10.1038/ncomms8389

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