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

Phesse, T.J. et al. (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. (doi: 10.1038/cdd.2014.15) (PMID:24583641) (PMCID:PMC4013513)

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: Articles
• Additional Information: This work was funded by Cancer Research UK, AICR, BBSRC and NH and MRC of Australia (#603127).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ridgway, Dr Rachel and Vousden, Karen and Sansom, Professor Owen
• 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., and Sansom, O.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Death and Differentiation
• Publisher: Springer Nature
• ISSN: 1350-9047
• ISSN (Online): 1476-5403
• Published Online: 28 February 2014
• Copyright Holders: Copyright © 2014 Macmillan Publishers Limited
• First Published: First published in Cell Death and Differentiation 21(6):956-966
• Publisher Policy: Reproduced under a Creative Commons license