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

Phesse, T. J. ORCID: https://orcid.org/0000-0001-9568-4916, Myant, K. B., Cole, A. M., Ridgway, R. A., Pearson, H. ORCID: https://orcid.org/0000-0002-3284-0843, Muncan, V., van den Brink, G. R., Vousden, K. H., Sears, R., Vassilev, L . T ., Clarke, A. R. ORCID: https://orcid.org/0000-0002-4281-426X and Sansom, O. J. 2014. Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo. Cell Death and Differentiation 21 (6) , pp. 956-966. 10.1038/cdd.2014.15

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (3MB) | Preview

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Additional Information:	This work is licensed under a Creative Commons Attribution 3.0 Unported License.
Publisher:	Nature Publishing Group
ISSN:	1350-9047
Date of First Compliant Deposit:	3 April 2019
Date of Acceptance:	8 January 2014
Last Modified:	08 May 2023 13:02
URI:	https://orca.cardiff.ac.uk/id/eprint/59028

Citation Data

Cited 70 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item