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, Luis A Martinez
NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2015
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-harbouri..View full abstract
Awarded by NCI
L.A.M. is supported by NCI CA166974-01A1. Flow cytometry experiments were performed at the UMMC Cancer Institute Flow Cytometry Core facility. We thank Dr Sibali Bandyopadhyay for assistance with Flow Cytometry Analysis. We thank Beverly Mitchell for providing the DCK promoter luciferase construct.