1. Regulation of p53 by Mdm2 E3 Ligase Function Is Dispensable in Embryogenesis and Development, but Essential in Response to DNA Damage
- Author
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Laura A. Tollini, Aiwen Jin, Jikyoung Park, and Yanping Zhang
- Subjects
Male ,Cancer Research ,MDMX ,DNA Repair ,DNA repair ,DNA damage ,Mutation, Missense ,Embryonic Development ,Mice, Transgenic ,medicine.disease_cause ,Radiation Tolerance ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins c-mdm2 ,Ubiquitin ,medicine ,Animals ,neoplasms ,030304 developmental biology ,0303 health sciences ,Mutation ,biology ,Ubiquitination ,Cell Biology ,Ubiquitin ligase ,Mice, Inbred C57BL ,enzymes and coenzymes (carbohydrates) ,Oncology ,Organ Specificity ,030220 oncology & carcinogenesis ,Proteolysis ,biology.protein ,Cancer research ,Mdm2 ,Female ,Protein Multimerization ,Tumor Suppressor Protein p53 ,DNA Damage ,Protein Binding - Abstract
Summary Mdm2 E3 ubiquitin ligase-mediated p53 degradation is generally accepted as the major mechanism for p53 regulation; nevertheless, the in vivo significance of this function has not been unequivocally established. Here, we have generated an Mdm2 Y487A knockin mouse; Mdm2 Y487A mutation inactivates Mdm2 E3 ligase function without affecting its ability to bind its homolog MdmX. Unexpectedly, Mdm2 Y487A/Y487A mice were viable and developed normally into adulthood. While disruption of Mdm2 E3 ligase function resulted in p53 accumulation, p53 transcriptional activity remained low; however, exposure to sublethal stress resulted in hyperactive p53 and p53-dependent mortality in Mdm2 Y487A/Y487A mice. These findings reveal a potentially dispensable nature for Mdm2 E3 ligase function in p53 regulation, providing insight that may affect how this pathway is targeted therapeutically.
- Published
- 2014
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