摘要
It is evident that p53 activity is critical for tumour prevention and stress response through its transcriptional activation of genes affecting cellular senescence, apoptosis, cellular metabolism, and DNA repair. The regulation of p53 is highly complex, and MDM2 and MDMX are thought to be critical for deciding the fate of p53, both through inhibitory binding and post-translational modification. Many mouse models have been generated to study the regulation of p53 in vivo, and they have altered our inter- pretations of how p53 is regulated by MDM2 and MDMX. Although MDM2 is absolutely required for p53 regulation, certain func- tions are dispensable under unstressed conditions, including the ability of MDM2 to degrade p53. MDMX, on the other hand, may only be required in select situations, like embryogenesis. These models have also clarified how cellular stress signals modify the p53-inhibiting activities of MDM2 and MDMX in vivo. It is clear that more work will need to be performed to further understand the contexts for each of these signals and the requirements of various MDM2 and MDMX functions. Here, we will discuss what we have learned from mouse modelling of MDM2 and MDMX and underscore the ways in which these models could inform future therapies.
基金
The authors would like to thank Hui Tian, Jing Yang, and Derek Franklin （Department of Radiation Oncology, University of North Carolina at Chapel Hill） for their helpful discussions of this manuscript. The authors apologize if they failed to cite any relevant articles. Funding This review was supported by grants from the National Institutes of Health （CA127770, CA 100302, and CA167637）, the Natural Science Foundation of China （NSFC） to Y.Z., and the National Institute of General Medical Sciences （5T32 GM007092） to N.R.T.
