title: The p53-Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans.
abstract: The extant jawless vertebrates, represented by lampreys and hagfish, are the oldest group of vertebrates and provide an interesting genomic evolutionary pivot point between invertebrates and jawed vertebrates. Through genome analysis of one of these jawless vertebrates, the Japanese lamprey (Lethenteron japonicum), we identified all three members of the important p53 transcription factor family--Tp53, Tp63, and Tp73--as well as the Mdm2 and Mdm4 genes. These genes and their products are significant cellular regulators in human cancer, and further examination of their roles in this most distant vertebrate relative sheds light on their origin and coevolution. Their important role in response to DNA damage has been highlighted by the discovery of multiple copies of the Tp53 gene in elephants. Expression of lamprey p53, Mdm2, and Mdm4 proteins in mammalian cells reveals that the p53-Mdm2 interaction and the Mdm2/Mdm4 E3 ligase activity existed in the common ancestor of vertebrates and have been conserved for >500 million years of vertebrate evolution. Lamprey Mdm2 degrades human p53 with great efficiency, but this interaction is not blocked by currently available small molecule inhibitors of the human HDM2 protein, suggesting utility of lamprey Mdm2 in the study of the human p53 signaling pathway.
authors.affiliation: p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore 138648;
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Coffill
authors.affiliation: Institute of Molecular and Cellular Biology, A*STAR, Singapore 138673;
authors.forename: Alison P
authors.initials: AP
authors.lastname: Lee
authors.affiliation: p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore 138648;
authors.forename: Jia Wei
authors.initials: JW
authors.lastname: Siau
authors.affiliation: p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore 138648;
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Chee
authors.affiliation: Bioinformatics Institute, A*STAR, Singapore 138671;
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Joseph
authors.affiliation: Bioinformatics Institute, A*STAR, Singapore 138671;
authors.forename: Yaw Sing
authors.initials: YS
authors.lastname: Tan
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India;
authors.forename: Arumugam
authors.initials: A
authors.lastname: Madhumalar
authors.affiliation: Institute of Molecular and Cellular Biology, A*STAR, Singapore 138673;
authors.forename: Boon-Hui
authors.initials: BH
authors.lastname: Tay
authors.affiliation: Institute of Molecular and Cellular Biology, A*STAR, Singapore 138673; Okinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa 904-0495, Japan;
authors.forename: Sydney
authors.initials: S
authors.lastname: Brenner
authors.affiliation: Bioinformatics Institute, A*STAR, Singapore 138671; School of Biological Sciences, Nanyang Technological University, Singapore 637551; Department of Biological Sciences, National University of Singapore, Singapore 117543;
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
authors.affiliation: p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore 138648;
authors.forename: Farid J
authors.initials: FJ
authors.lastname: Ghadessy
authors.affiliation: Institute of Molecular and Cellular Biology, A*STAR, Singapore 138673; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Byrappa
authors.initials: B
authors.lastname: Venkatesh
authors.affiliation: p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore 138648;
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D017124:Conserved Sequence; D016678:Genome; D006801:Humans; D007798:Lampreys / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000378:metabolism*; D010802:Phylogeny; D011485:Protein Binding; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Mdm2; Mdm4; evolution; lamprey; p53