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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.

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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.
Beatson Institute for Cancer Research, Glasgow, UK.
School of Biosciences, University of Cardiff.CF10 3US, Cardiff, UK.
Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Discovery Oncology, Roche Research Center, Nutley, NJ, USA.


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.

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