title: Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo.
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.
authors.affiliation: 1] School of Biosciences, University of Cardiff.CF10 3US, Cardiff, UK [2] Ludwig Institute for Cancer Research, Melbourne, Australia [3] The Walter and Eliza Hall Institute for Medical Research, Melbourne, Australia [4] Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Phesse
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: K B
authors.initials: KB
authors.lastname: Myant
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Cole
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Ridgway
authors.affiliation: School of Biosciences, University of Cardiff.CF10 3US, Cardiff, UK.
authors.forename: H
authors.initials: H
authors.lastname: Pearson
authors.affiliation: Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Muncan
authors.affiliation: Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: G R
authors.initials: GR
authors.lastname: van den Brink
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: K H
authors.initials: KH
authors.lastname: Vousden
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sears
authors.affiliation: Discovery Oncology, Roche Research Center, Nutley, NJ, USA.
authors.forename: L T
authors.initials: LT
authors.lastname: Vassilev
authors.affiliation: School of Biosciences, University of Cardiff.CF10 3US, Cardiff, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Clarke
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: O J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin