title: Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability.
abstract: Mdm2 and Mdm4 are homologous RING domain-containing proteins that negatively regulate the tumor suppressor p53 under physiological and stress conditions. The RING domain of Mdm2 encodes an E3-ubiquitin ligase that promotes p53 degradation. In addition, Mdm2 and Mdm4 interact through their respective RING domains. The in vivo significance of Mdm2-Mdm4 heterodimerization in regulation of p53 function is unknown. In this study, we generated an Mdm4 conditional allele lacking the RING domain to investigate its role in Mdm2 and p53 regulation. Our results demonstrate that homozygous deletion of the Mdm4 RING domain results in prenatal lethality. Mechanistically, Mdm2-Mdm4 heterodimerization is critical for inhibiting lethal p53 activation during early embryogenesis. However, Mdm2-Mdm4 interaction is dispensable for regulating p53 activity as well as the stability of Mdm2 and p53 at later stages of development. We propose that Mdm4 is a key cofactor of Mdm2 that inhibits p53 activity primarily during early embryogenesis but is dispensable for regulating p53 and Mdm2 stability in the adult mouse.
authors: Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Vinod
authors: V
authors: Pant
authors: Shunbin
authors: S
authors: Xiong
authors: Tomoo
authors: T
authors: Iwakuma
authors: Alfonso
authors: A
authors: Quintás-Cardama
authors: Guillermina
authors: G
authors: Lozano
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D002588:Cesium Radioisotopes; D017931:DNA Primers / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic; D055503:Protein Multimerization / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002588:Cesium Radioisotopes; D017931:DNA Primers; C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases