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Genes Dev. 2016 Feb 1;30(3):281-92. doi: 10.1101/gad.274118.115. Epub 2016 Jan 21.

The p53-Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans.

Author information

1
p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore 138648;
2
Institute of Molecular and Cellular Biology, A*STAR, Singapore 138673;
3
Bioinformatics Institute, A*STAR, Singapore 138671;
4
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India;
5
Institute of Molecular and Cellular Biology, A*STAR, Singapore 138673; Okinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa 904-0495, Japan;
6
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;
7
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.

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.

KEYWORDS:

Mdm2; Mdm4; evolution; lamprey; p53

PMID:
26798135
PMCID:
PMC4743058
DOI:
10.1101/gad.274118.115
[Indexed for MEDLINE]
Free PMC Article
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