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

• Published in: Cell death and differentiation 2014-06, Vol.21 (6), p.956-966
• Main Authors: Phesse, T J, Myant, K B, Cole, A M, Ridgway, R A, Pearson, H, Muncan, V, van den Brink, G R, Vousden, K H, Sears, R, Vassilev, L T, Clarke, A R, Sansom, O J
• Format: Article
• Language: English
• Subjects: 631/337/1427; 631/80/82/23; 631/80/86; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - radiation effects; Biochemistry; Biomedical and Life Sciences; Cancer research; Cell Biology; Cell cycle; Cell Cycle Analysis; Cell death; Cell Survival - drug effects; Cisplatin - administration & dosage; Colorectal cancer; Cytotoxicity; DNA damage; DNA Damage - drug effects; DNA Damage - radiation effects; Enterocytes - drug effects; Enterocytes - metabolism; Enterocytes - radiation effects; Humans; Life Sciences; Medical research; Mice; Original Paper; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Radiation, Ionizing; Stem Cells; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/cdd.2014.15

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.