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

Phesse, TJ; Myant, KB; Cole, AM; Ridgway, RA; Pearson, H; Muncan, V; van den Brink, GR; Vousden, KH; Sears, R; Vassilev, LT; Clarke, AR; Sansom, OJ

Author(s): Phesse, TJ; Myant, KB; Cole, AM; Ridgway, RA; Pearson, H; Muncan, V; van den Brink, GR; Vousden, KH; Sears, R; Vassilev, LT; Clarke, AR; Sansom, OJ;
Details: Publication Year 2014-06,Volume 21,Issue #6,Page 956-66
Journal Title: Cell Death Differ
Publication Type: Journal Article
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.
Publisher: NPG
Research Division(s): Cell Signalling And Cell Death
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013513/
Publisher's Version: https://doi.org/10.1038/cdd.2014.15
Open Access at Publisher's Site: http://www.nature.com/cdd/journal/v21/n6/full/cdd201415a.html
Terms of Use/Rights Notice: This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/.

Creation Date: 2014-06-02 11:08:26