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

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. 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

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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)
Publisher:	Nature Publishing Group
ISSN:	1350-9047
Date of First Compliant Deposit:	3 April 2019
Date of Acceptance:	8 January 2014
Last Modified:	15 Jul 2020 14:05
URI:	http://orca.cf.ac.uk/id/eprint/59028

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