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Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo

Research output: Contribution to journalArticlepeer-review

  • T J Phesse
  • K B Myant
  • A M Cole
  • R A Ridgway
  • H Pearson
  • V Muncan
  • G R van den Brink
  • K H Vousden
  • R Sears
  • L T Vassilev
  • A R Clarke
  • O J Sansom

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)956-966
Number of pages11
JournalCell Death and Differentiation
Volume21
Issue number6
Early online date28 Feb 2014
DOIs
Publication statusPublished - Jun 2014

Abstract

Recent studies have suggested that C-MYC may be an excellent therapeutic cancer target and a number of new agents targeting C-MYC are in preclinical development. Given most therapeutic regimes would combine C-MYC inhibition with genotoxic damage, it is important to assess the importance of C-MYC function for DNA damage signalling in vivo. In this study, we have conditionally deleted the c-Myc gene in the adult murine intestine and investigated the apoptotic response of intestinal enterocytes to DNA damage. Remarkably, c-Myc deletion completely abrogated the immediate wave of apoptosis following both ionizing irradiation and cisplatin treatment, recapitulating the phenotype of p53 deficiency in the intestine. Consistent with this, c-Myc-deficient intestinal enterocytes did not upregulate p53. Mechanistically, this was linked to an upregulation of the E3 Ubiquitin ligase Mdm2, which targets p53 for degradation in c-Myc-deficient intestinal enterocytes. Further, low level overexpression of c-Myc, which does not impact on basal levels of apoptosis, elicited sustained apoptosis in response to DNA damage, suggesting c-Myc activity acts as a crucial cell survival rheostat following DNA damage. We also identify the importance of MYC during DNA damage-induced apoptosis in several other tissues, including the thymus and spleen, using systemic deletion of c-Myc throughout the adult mouse. Together, we have elucidated for the first time in vivo an essential role for endogenous c-Myc in signalling DNA damage-induced apoptosis through the control of the p53 tumour suppressor protein.

    Research areas

  • Animals, Apoptosis, Cell Survival, Cisplatin, DNA Damage, Enterocytes, Humans, Mice, Proto-Oncogene Proteins c-myc, Radiation, Ionizing, Tumor Suppressor Protein p53

ID: 25035516