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

被引:82
|
作者
Phesse, T. J. [1 ,2 ,3 ,4 ]
Myant, K. B. [5 ]
Cole, A. M. [5 ]
Ridgway, R. A. [5 ]
Pearson, H. [1 ]
Muncan, V. [6 ]
van den Brink, G. R. [6 ]
Vousden, K. H. [5 ]
Sears, R. [7 ]
Vassilev, L. T. [8 ]
Clarke, A. R. [1 ]
Sansom, O. J. [5 ]
机构
[1] Cardiff Univ, Sch Biosci, Cardiff CF10 3US, S Glam, Wales
[2] Ludwig Inst Canc Res, Melbourne, Vic 3050, Australia
[3] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia
[4] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia
[5] Beatson Insitute Canc Res, Glasgow G61 1BD, Lanark, Scotland
[6] Leiden Univ, Dept Gastroenterol & Hepatol, Med Ctr, Leiden, Netherlands
[7] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
[8] Roche Res Ctr, Nutley, NJ USA
来源
CELL DEATH AND DIFFERENTIATION | 2014年 / 21卷 / 06期
基金
英国生物技术与生命科学研究理事会;
关键词
MYC; DNA damage; apoptosis; P53; MDM2; in vivo; TRANSCRIPTIONAL TARGET; INTESTINAL EPITHELIUM; EMBRYONIC LETHALITY; MDM2-DEFICIENT MICE; GAMMA-IRRADIATION; CANCER-THERAPY; P53; PATHWAY; MDM2; ACTIVATION;
D O I
10.1038/cdd.2014.15
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:956 / 966
页数:11
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