title: Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities.
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.
authors.affiliation: Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Kollareddy
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dimitrova
authors.affiliation: Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Krishna C
authors.initials: KC
authors.lastname: Vallabhaneni
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chan
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA.
authors.forename: Thuc
authors.initials: T
authors.lastname: Le
authors.affiliation: Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Chauhan
authors.affiliation: Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Zunamys I
authors.initials: ZI
authors.lastname: Carrero
authors.affiliation: Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Gopalakrishnan
authors.initials: G
authors.lastname: Ramakrishnan
authors.affiliation: Department of Microbiology and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
authors.affiliation: 1] Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Locked Bag, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia [3] Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Ygal
authors.initials: Y
authors.lastname: Haupt
authors.affiliation: 1] Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Locked Bag, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Haupt
authors.affiliation: Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Pochampally
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Boss
authors.affiliation: Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Damian G
authors.initials: DG
authors.lastname: Romero
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA.
authors.forename: Caius G
authors.initials: CG
authors.lastname: Radu
authors.affiliation: Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D003842:Deoxycytidine Kinase; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006160:Guanosine Triphosphate; D006801:Humans; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D009705:Nucleosides / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D009705:Nucleosides; D009711:Nucleotides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006160:Guanosine Triphosphate; D003842:Deoxycytidine Kinase