Elephant genes could hold clues to reducing cancer risk, a new study has found.
A study team from seven research institutions, including the University of Oxford and the University of Edinburgh, UK, found that 20 different molecules unique to elephants get activated for increased sensitivity and response against carcinogenic conditions.
They used bioinformatic modelling to investigate the molecular interactions of the p53 protein, which is known to give protection against cancers, and their findings into molecular interactions could benefit the human population.
The research, published in Molecular Biology and Evolution, looked at why elephants’ high resistance to cancer is linked to their 20 copies of the p53 gene, compared with the single p53 gene found in other mammals.
P53 plays a key role in regulating the repairing mechanisms of the DNA and suppresses uncontrolled cell growth.
Each of the elephant’s 40 alleles from the 20 p53 genes is structurally slightly different, which gives them a wider range of molecular anti-cancer interactions than a human, the researchers say.
Using biochemical analysis and computer simulations, the researchers found key differences in the regulated interaction between the elephant’s different p53 isoforms and the oncogene MDM2 E3 ubiquitin ligase.
As a result of the changes in coding sequences and molecular structure, a number of p53s escaped the interaction with MDM2 that would normally result in their inactivation.
The research team say it is the first time it has been demonstrated that the different p53 isoforms found in the elephant do not get degraded or inactivated by MDM2.
Co-author Professor Robin Fåhraeus, from INSERM, Paris said: “This is an exciting development for our understanding of how p53 contributes to preventing cancer development.
“In humans, the same p53 protein is responsible for deciding if 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 shed new light on p53’s tumour suppressor activity.”
Co-author Professor Fritz Vollrath, Oxford University and trustee of Save the Elephants, added: “This intricate and intriguing study demonstrates how much more there is to elephants than impressive size and how important it is that we not only conserve but also study these signature animals in minute detail. After all, their genetics and physiology are all driven by evolutionary history as well as today’s ecology, diet and behaviour.”
Padariya M, Jooste M-L, Hupp T et al. The Elephant evolved p53 isoforms that escape mdm2-mediated repression and cancer. Molecular Biology and Evolution 6 July 2022
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