Elephant genes can be the key to avoiding cancer

Researchers modeling the cancer-suppressing p53 gene identify how the 20 different molecules unique to elephants are activated for increased sensitivity and response to carcinogenic conditions – with implications for cancer treatments in humans.

Researchers from seven research institutes, including the University of Oxford and the University of Edinburgh, have used cutting-edge bioinformatics modeling to study the molecular interactions between the p53 protein, which is known to provide protection against cancer.

The research, published in Molecular Biology and Evolution, provides new insights into molecular interactions that can help people become less likely to get cancer.

Cells are routinely replicated, with new cells replacing the old ones, and each new cell containing new copies of the DNA. These new cells should be exact copies of the older cells, but mutations occur if proteins mistakenly replicate and transcribe DNA. Most defects are repaired immediately by the cell, although the number of mutations and the quality of repairs are affected by both genetic and external / living circumstances. Toxic compounds, stress, poor living conditions and aging can all increase the rate of mutation.

Tumors resulting from the accumulation of such gene mutations increase in risk with age – but unlike humans, elephants appear to counteract this trend. Despite their large body size and life expectancy comparable to humans, cancer mortality in elephants is estimated at less than 5% (instead of up to 25% in humans). Researchers link elephants’ high resistance to cancer to their 20 copies of the p53 gene – the ‘guardian of the genome’ – compared to the single p53 gene found in other mammals.

Co-author Professor Fritz Vollrath, Department of Biology, Oxford University and administrator of Save the Elephants said: ‘This intricate and exciting study shows how much more there is about elephants than impressive size, and how important it is that we not only preserve, but also study these signature animals in the smallest detail. After all, their genetics and physiology are all driven by evolutionary history as well as today’s ecology, diet, and behavior. ‘

P53 plays a key role in regulating DNA repair mechanisms and suppresses uncontrolled cell growth. The protein is activated when DNA is damaged, helping to orchestrate a reaction that stops DNA replication and repairs any uncorrected copies of the cell. In replicated cells with undamaged DNA, the p53 repair activity is unnecessary and is inactivated by another protein, the oncogenic MDM2 E3 ubiquitin ligase.

The regulated interaction, or handshake, between p53 – MDM2 is essential for healthy cells to divide and replicate, damaged cells to be repaired and the destruction of cells with failed repairs or extensive damage.

The elephant may appear genetically over-equipped with 40 alleles or versions from its twenty p53 genes, but each is structurally slightly different, giving an elephant a much wider range of molecular anti-cancer interactions than a human with only two alleles from a single gene.

Using biochemical analyzes and computer simulations, the researchers found key differences in the handshake interaction between the elephant’s different p53 isoforms and MDM2.

The minor variations in molecular sequence result in a different molecular structure for each of the p53 molecules. The small structural differences change the three-dimensional shape of the isoform and significantly change the handshake function between p53 and MDM2.

The research team found that as a result of the changes in coding sequences and molecular structure, a number of p53 escaped the interaction with MDM2 that would normally result in their inactivation. The results are the first to show that the various p53 isoforms found in the elephant are not degraded or inactivated by MDM2 – unlike in humans.

Co-author Professor Robin FĂ„hraeus, INSERM, Paris said: ‘This is an exciting development for our understanding of how p53 helps prevent cancer development. In humans, the same p53 protein is responsible for deciding whether cells should stop proliferating or go into apoptosis, but how p53 makes this decision has been difficult to elucidate. The existence of several p53 isoforms in elephants with different capacities to interact with MDM2 offers an exciting new approach to shedding new light on p53’s tumor suppressive activity. ‘

Understanding more about how p53 molecules are activated and when this can lead to increased sensitivity and response to carcinogenic conditions is an exciting prospect for further research into the activation of p53 and targeted drug therapies in humans.

The corresponding author, Dr. Konstantinos Karakostis, Autonomous University of Barcelona noted: “Conceptually, the accumulation of structurally modified p53 pools that collectively or synergistically co-regulate the responses to different loads in the cell establishes an alternative mechanistic model of cell regulation with high potential significance for biomedical applications. ‘

The entire paper, ‘The elephant developed p53 isoforms that escape mdm2-mediated suppression and cancer’ is available in Molecular Biology and Evolution.

Leave a Comment