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Cell Death Differ. 2014 Jun;21(6):956-66. doi: 10.1038/cdd.2014.15. Epub 2014 Feb 28.

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

Author information

1
1] School of Biosciences, University of Cardiff.CF10 3US, Cardiff, UK [2] Ludwig Institute for Cancer Research, Melbourne, Australia [3] The Walter and Eliza Hall Institute for Medical Research, Melbourne, Australia [4] Department of Medical Biology, University of Melbourne, Melbourne, Australia.
2
Beatson Institute for Cancer Research, Glasgow, UK.
3
School of Biosciences, University of Cardiff.CF10 3US, Cardiff, UK.
4
Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
5
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
6
Discovery Oncology, Roche Research Center, Nutley, NJ, USA.

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.

PMID:
24583641
PMCID:
PMC4013513
DOI:
10.1038/cdd.2014.15
[Indexed for MEDLINE]
Free PMC Article

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