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

Autor:	Kollareddy M; Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA., Dimitrova E; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA., Vallabhaneni KC; Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA., Chan A; Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA., Le T; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA., Chauhan KM; Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA., Carrero ZI; Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA., Ramakrishnan G; Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA., Watabe K; Department of Microbiology and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA., Haupt Y; 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., Haupt S; 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., Pochampally R; Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA., Boss GR; Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA., Romero DG; Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA., Radu CG; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA., Martinez LA; Department of Biochemistry and University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2015 Jun 12; Vol. 6, pp. 7389. Date of Electronic Publication: 2015 Jun 12.
DOI:	10.1038/ncomms8389
Abstrakt:	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.
Databáze:	MEDLINE
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