Mdm2 and MdmX partner to regulate p53.
Mdm2 regulates the stability, translation, subcellular localization and transcriptional activity of p53 protein. Mdm2-dependent p53 inhibition is essential in regulating p53 activity during embryonic development and in adult tissues. MdmX, an Mdm2 homolog, is also essential for p53 inhibition in vivo. Recent advances in the field from biochemical and genetic studies have revealed an essential role for the MdmX RING domain in Mdm2-dependent p53 polyubiquitination and degradation. Mdm2 on its own is a monoubiquitin E3 ligase for p53, but is converted to a p53 polyubiquitin E3 ligase by MdmX through their RING-RING domain interactions. MdmX acts as an activator as well as a substrate of Mdm2/MdmX E3 complex. The insufficiency of Mdm2 for p53 polyubiquitination also demands other p53 E3 ligases or E4 factors be incorporated into the p53 degradation arena. Deubiquitinases nullify the effects of E3 actions and reverse the ubiquitination process, which permits a diverse and dynamic pattern of p53 stability control. Unsurprisingly, stress signals target MdmX to disengage the p53/Mdm2 feedback loop for timely and appropriate p53 responses to these stresses.
Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. xinjiang.wang@roswellpark.org
Xinjiang
X
Wang
Xuejun
X
Jiang
D000818:Animals; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases