Regulation of p53 by Mdm2 E3 Ligase Function Is Dispensable in Embryogenesis and Development, but Essential in Response to DNA Damage

• Mdm2Y487A loses E3 ligase activity for p53 degradation, but retains MdmX binding
• Robust Mdm2 E3 ligase function is dispensable for embryogenesis and development
• In vivo, Mdm2Y487A mutation results in increased p53 stability, but not activity
• Mdm2Y487A/Y487A mice demonstrate p53-dependent hyperradiosensitivity

SummaryMdm2 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 Mdm2Y487A knockin mouse; Mdm2Y487A mutation inactivates Mdm2 E3 ligase function without affecting its ability to bind its homolog MdmX. Unexpectedly, Mdm2Y487A/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 Mdm2Y487A/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.

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