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.

The p53 gene family in vertebrates: Evolutionary considerations

“…The numbers at the sides of each sequence indicate the respective length whereas the numbers below the boxes indicate the length of the domain. The three sequences of the Japanese lamprey Lethenteron camtschaticum are positioned separately in the figure because their attribution (Coffill et al, ) does not agree with the phylogenetic analysis conducted in this study…”

“…Colored boxes indicate conserved syntenic regions; highlighted gene names are helpful to identify ortholog genes in regions less conserved. The three sequences of the Japanese lamprey Lethenteron camtschaticum are positioned separately in the figure because their attribution (Coffill et al, ) does not agree with the phylogenetic analysis conducted in this study [Color figure can be viewed at wileyonlinelibrary.com]…”

“…These duplications in the lamprey may be due to lineagespecific whole genome duplication events (Fried, Prohaska, & Stadler, 2003). The lamprey genes identified by Coffill et al (2016) as TP63 and TP53 have obvious differences; in fact the OD domain of TP63 did not showed the same secondary structure found in the other analyzed organisms and a gene has lost the SAM domain. Thus the lack of such domain in this lamprey gene and in the gnathostome TP53 genes would constitute a case of evolutionary convergence.…”

“…Microsyntenic analysis was carried out on the genomes of organisms belonging to the main lineages of gnathostomes while for the jawless L. camtschaticum was obtained fromCoffill et al (2016) (Figure 2).F I G U R E 1 The phylogenetic analysis of p53 gene family. Bayesian Inference on 55 protein sequences.…”

p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30

“…Among these, the control of programmed cell death is often considered to be the most relevant for tumor suppression (Bieging et al, 2014). Seminal studies in mouse models, as well as evidence from the evolutionary story of the p53 pathway, have established that unrestrained p53 function can lead to massive cell death (Coffill et al, 2016;Montes de Oca Luna et al, 1995). The identification of a negative feedback loop, comprising p53 and its target and repressor MDM2 (Barak et al, 1993;Harris and Levine, 2005;Momand et al, 1992) exemplifies the evolutionary pressure to select for balanced p53 activity.…”