P53 suppresses ribonucleotide reductase via inhibiting mTORC1

Zhengfu He, Xing Hu, Weijin Liu, Adrienne Dorrance, Ramiro Garzon, Peter J. Houghton, Changxian Shen

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Balanced deoxyribonucleotides pools are essential for cell survival and genome stability. Ribonucleotide reductase is the rate-limiting enzyme for the production of deoxyribonucleotides. We report here that p53 suppresses ribonucleotide reductase subunit 1 (RRM1) and 2 (RRM2) via inhibiting mammalian target of rapamycin complex 1 (mTORC1). In vitro, cancer cell lines and mouse embryonic fibroblast cells were treated with different concentrations of pharmacological inhibitors for different times. In vivo, rhabdomyosarcoma Rh30 cell tumor-bearing mice were treated with rapamycin or AZD8055. Protein levels and phosphorylation status were assessed by immunoblotting and mRNA levels were determined by real time RT-PCR. Pharmacological inhibition of mTORC1 with rapamycin, mTOR kinase with AZD8055 or protein kinase B with MK2206 resulted in decrease of RRM1 and RRM2 in Rh30 cells both in vitro and in mouse tumor xenografts. Moreover, eukaryotic translational initiation factor 4E-binding proteins 1 and 2 double knockout mouse embryonic fibroblast cells demonstrated an elevation of RRM1 and RRM2. Furthermore, downregulation of mTOR-protein kinase B signaling or cyclin dependent kinase 4 led to decrease of RRM1 and RRM2 mRNAs. In addition, TP53 mutant cancer cells had elevation of RRM1 and RRM2, which was reduced by rapamycin. Importantly, human double minute 2 inhibitor nutlin-3 decreased RRM1 and RRM2 in TP53 wild type rhabdomyosarcoma Rh18 but not in TP53 mutated Rh30 cells. Our data demonstrated that mTOR enhances the cap-dependent protein translation and gene transcription of RRM1 and RRM2. Our findings might provide an additional mechanism by which p53 maintains genome stability.

Original languageEnglish (US)
Pages (from-to)41422-41431
Number of pages10
JournalOncotarget
Volume8
Issue number25
DOIs
StatePublished - 2017

Keywords

  • Deoxyribonucleotides (dNTPs)
  • Mammalian target of rapamycin (mTOR)
  • Nutlin-3
  • P53
  • Ribonucleotide reductase (RNR)

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    He, Z., Hu, X., Liu, W., Dorrance, A., Garzon, R., Houghton, P. J., & Shen, C. (2017). P53 suppresses ribonucleotide reductase via inhibiting mTORC1. Oncotarget, 8(25), 41422-41431. https://doi.org/10.18632/oncotarget.17440