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  current news   Press   selected story    
     
  22 January 2016  
 
The p53-Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans
 
 




Authors
Cynthia R. Coffill1*, Alison P. Lee2*, Jia Wei Siau1, Sharon M. Chee1, Thomas L. Joseph3, Yaw Sing Tan3, Arumugam Madhumalar4, Boon-Hui Tay2, Sydney Brenner2, Chandra S.Verma3,5,6, Farid J. Ghadessy1, Byrappa Venkatesh2,7,† and David P. Lane1,†

1 p53 Laboratory (p53Lab), Agency for Science, Technology and Research (A*STAR), #06-06, Immunos,    8A Biomedical Grove, Singapore, 138648
2 Institute of Molecular and Cellular Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 138673
3 Bioinformatics Institute, A*STAR, #07-01 Matrix, 30 Biopolis Street, Singapore 138671
4 National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
5 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore
6 Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543    Singapore
7 Department of Paediatrics, Yong Loo Lin, School of Medicine, National University of Singapore,    Singapore 119228

*equal contribution
†Corresponding authors

Published online in Genes & Development on 21 Jan 2016.

Abstract
The extant jawless vertebrates, represented by lampreys and hagfishes, 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 have 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 co-evolution. 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 over 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. 

Figure 1. Japanese lamprey (Lethenteron japonicum) and its sucker-like mouth. Lampreys are ancient vertebrates that lack jaws and teeth, and instead possess a sucker-like mouth which is used for attaching to large fishes and sucking their blood and body fluid.

Figure 2. (A) Protein sequence alignment of the p53-binding region of Mdm2 from lamprey, Eshark (elephant shark, G9J1M1), zebrafish (Q561Z0), frog (P56273), chicken (F1NGX6), mouse (Q569X0) and human (Q00987) (corresponding to human protein residues 1–110). (B) Protein sequence alignment of Mdm2 interacting region of p53 sequences from lamprey, elephant shark (G9J1L8), zebrafish (P79734), frog (P07193), chicken (P10360), mouse (Q549C9) and human (P04637) (corresponding to human protein residues 16-30). (C) Western blot showing in vitro translation (IVT) and immunoprecipitation (IP) of human and lamprey p53 (top panel) by either HDM2 or Lj-Mdm2, which were used as bait. Input levels can be seen in the lower panel.


For more information on Byrappa VENKATESH 's lab, please click here.