title: p53 regulation: teamwork between RING domains of Mdm2 and MdmX.
abstract: p53 is a major tumor suppressor frequently inactivated through direct gene mutation and alternative mechanisms including overexpression of Mdm2 and MdmX. Both Mdm2 and MdmX are essential for negative regulation of p53 in vivo in a mutually dependent manner. The RING domain dependent E3 ligase activity of Mdm2 has been shown to be essential for negative regulation of p53. The prevailing model has dubbed MdmX as an inhibitor of p53 transcriptional activity through direct binding of its N-terminal domain to p53. However, recent findings established an essential role of the RING domain of MdmX in p53 degradation in vitro and in vivo. Biochemically, Mdm2 on its own is a monoubiquitinatuion E3 ligase, however, MdmX can convert Mdm2 into a polyubiquitination E3 ligase necessary for p53 proteasomal degradation in cells, through their RING-RING interactions. While Mdm2 is the catalytic components of Mdm2/MdmX E3 complex, MdmX is both the activating component and a substrate of the holoenzyme. Knock-in of RING mutant MdmX in mice causes p53-dependent embryonic lethality in a similar manner as knockout of MdmX whole gene. The new advance of the field assigned an essential role of the RING domain of MdmX in negative regulation of p53 in vivo, just like Mdm2 RING domain, through p53 degradation.
authors: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA. xinjiang.wang@roswellpark.org
authors: Xinjiang
authors: X
authors: Wang
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D058570:TOR Serine-Threonine Kinases