Tumors result from an accumulation of gene mutations that increase risk with age. However, unlike humans, elephants seem to buck this trend. Despite their large body size and a life expectancy comparable to humans, cancer mortality in elephants is estimated at less than 5% (rather than up to 25% in humans).
Elephants have 20 copies of the p53 gene, known as the “guardian of the genome.” According to scientists, elephants’ high resistance to cancer is linked to these genes.
In a new study, scientists from seven research institutions, including the University of Oxford and the University of Edinburgh, used pioneering bioinformatic modeling to identify the molecular interactions of the p53 protein known to give protection against cancers.
P53 regulates the repairing mechanisms of the DNA. It also stops uncontrolled cell growth. Activation of this protein occurs when DNA is damaged. Upon activation, it helps orchestrate a response that pauses 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 oncogene MDM2 E3 ubiquitin ligase.
Healthy cells proliferating and replicating, repairing damaged cells, and eliminating cells with failed repairs or substantial damage depend on the regulated interaction, or “handshake,” between the p53 and MDM2.
Elephants seem to have 40 alleles, or versions, from its twenty p53 genes, but each is structurally slightly different. This gives elephants a broader range of molecular anti-cancer interactions than humans with just two alleles from a single gene.
Thanks to biochemical analysis and computer simulations, scientists could distinguish the handshake interaction between the elephant’s different p53 isoforms and the MDM2. They found that the minor variations in molecular sequence cause different molecular structures for each of the p53 molecules. The minor structural variations considerably change the isoform’s three-dimensional structure and the handshake between p53 and MDM2.
The research team found that, due to the changes in coding sequences and molecular structure, several p53 escaped the interaction with MDM2 that would normally result in their inactivation.
Co-author Professor Robin Fåhraeus, 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 tumor suppressor activity.”
Corresponding author, Dr. Konstantinos Karakostis, Autonomous University of Barcelona, noted: “Conceptually, the accumulation of structurally modified p53 pools, collectively or synergistically co-regulating the responses to diverse stresses in the cell, establishes an alternative mechanistic model of cell regulation of high potential significance to biomedical applications.”
Journal Reference:
- Monikaben Padariya, Mia-Lyn Jooste et al. The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer. Molecular Biology and Evolution, Volume 39, Issue 7, July 2022, msac149. DOI: 10.1093/molbev/msac149