One of the best known cellular tumor suppression systems evolved more than a billion years ago, far earlier than previously thought, research results from A*STAR’s p53 Laboratory and Bioinformatics Institute suggest. A team led by Sir David Lane has found the p53 gene and its regulator Mdm2 to be present in placozoans, the simplest known, free-living, multicellular, invertebrate animal1. The work not only provides greater understanding of the history of an important, highly conserved genetic pathway, but also opens up a useful system for examination and experimentation in the laboratory.
The p53 protein plays a pivotal anticancer role in cells. It can stabilize damaged DNA by activating repair proteins and regulating the cell cycle to allow these proteins time to work. Until an emergency, p53 is kept at low levels by Mdm2, which binds to p53 to prevent it from acting and then initiates its degradation. All vertebrate animals sequenced to date have p53 and Mdm2 genes, but two invertebrates used as genetic model organisms—the fruit fly, Drosophila melanogaster and the nematode worm, Caenorhabditis elegans—have only the p53 gene.
Lane and his co-workers searched the recently sequenced genome of the only known species of placozoan2, Trichoplax adhaerens (Fig. 1), for genes similar to human Mdm2 and p53. They used BLAST software that detects regions of similarity between the sequences in genomes.
In the placozoan genome, they found matching genes carrying identical amino acids in more than 20% of the same positions. In several domains of the placozoan genes, where compounds that can activate p53 are bound, the sequences were even more similar. This implies that the placozoan p53 and Mdm2 genes interact with similar compounds, and suggests that the entire tumor suppression pathway has been evolutionarily conserved.
Interestingly, p53 in the placozoan is much closer in sequence to human p53 than either the fruit fly or the nematode. Since the equivalent of Mdm2 has not been found in the latter two species, the researchers suggest that they may well have diverged from the ancestral tumor suppression system, losing key elements of the pathway in the process.
As Trichoplax can be cultured easily in the laboratory, and has such a small genome, Lane and his co-workers propose to use it to trace elements of the pathway that are not encoded in the genes, such as where p53 binds to the DNA. They also want to determine how the p53-system works in each of the four Trichoplax cell types.