title: The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo.
abstract: There are currently two distinct models proposed to explain why both MDM2 and MDMX are required in p53 control, with a key difference centered on whether these two p53 inhibitors work together or independently. To test these two competing models, we generated knockin mice expressing a point mutation MDMX mutant (C462A) that is defective in MDM2 binding. This approach allowed a targeted disassociation of the MDM2/MDMX heterocomplex without affecting the ability of MDMX to bind to p53, and while leaving the MDM2 protein itself completely untouched. Significantly, Mdmx(C462A/C462A) homozygous mice died at approximately day 9.5 of embryonic development, as the result of a combination of apoptosis and decreased cell proliferation, as shown by TUNEL and BrdU incorporation assays, respectively. Interestingly, even though the MDMX mutant protein abundance was found slightly elevated in the Mdmx(C462A/C462A) homozygous embryos, both the abundance and activity of p53 were markedly increased. A p53-dependent death was demonstrated by the finding that concomitant deletion of p53 completely rescued the embryonic lethality in Mdmx(C462A/C462A) homozygous mice. Our data demonstrate that MDM2 and MDMX function as an integral complex in p53 control, providing insights into the nonredundant nature of the function of MDM2 and MDMX.
authors: Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. leihuang@shsmu.edu.cn
authors: Lei
authors: L
authors: Huang
authors: Zheng
authors: Z
authors: Yan
authors: Xiaodong
authors: X
authors: Liao
authors: Yuan
authors: Y
authors: Li
authors: Jie
authors: J
authors: Yang
authors: Zhu-Gang
authors: ZG
authors: Wang
authors: Yong
authors: Y
authors: Zuo
authors: Hidehiko
authors: H
authors: Kawai
authors: Miriam
authors: M
authors: Shadfan
authors: Suthakar
authors: S
authors: Ganapathy
authors: Zhi-Min
authors: ZM
authors: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D005786:Gene Expression Regulation / Q000235:genetics*; D055879:Gene Knock-In Techniques; D005838:Genotype; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D046912:Multiprotein Complexes; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D001973:Bromodeoxyuridine