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

Author

Listed:
  • 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
    Present address: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA)

  • Ygal Haupt

    (Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Locked Bag, East Melbourne, Victoria 3002, Australia
    The University of Melbourne
    The University of Melbourne)

  • Sue Haupt

    (Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Locked Bag, East Melbourne, Victoria 3002, Australia
    The University of Melbourne)

  • 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)

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.

Suggested Citation

  • Madhusudhan Kollareddy & Elizabeth Dimitrova & Krishna C. Vallabhaneni & Adriano Chan & Thuc Le & Krishna M. Chauhan & Zunamys I. Carrero & Gopalakrishnan Ramakrishnan & Kounosuke Watabe & Ygal Haupt , 2015. "Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8389
    DOI: 10.1038/ncomms8389
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    Cited by:

    1. Louis Verny & Nadir Sella & Séverine Affeldt & Param Priya Singh & Hervé Isambert, 2017. "Learning causal networks with latent variables from multivariate information in genomic data," PLOS Computational Biology, Public Library of Science, vol. 13(10), pages 1-25, October.
    2. Camilla Tombari & Alessandro Zannini & Rebecca Bertolio & Silvia Pedretti & Matteo Audano & Luca Triboli & Valeria Cancila & Davide Vacca & Manuel Caputo & Sara Donzelli & Ilenia Segatto & Simone Vodr, 2023. "Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Donglin Ding & Alexandra M. Blee & Jianong Zhang & Yunqian Pan & Nicole A. Becker & L. James Maher & Rafael Jimenez & Liguo Wang & Haojie Huang, 2023. "Gain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Anna Bianchi-Smiraglia & David W. Wolff & Daniel J. Marston & Zhiyong Deng & Zhannan Han & Sudha Moparthy & Rebecca M. Wombacher & Ashley L. Mussell & Shichen Shen & Jialin Chen & Dong-Hyun Yun & Ande, 2021. "Regulation of local GTP availability controls RAC1 activity and cell invasion," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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