The p53 tumour suppressor is a transcription factor with roles in cell development, apoptosis, oncogenesis, ageing and homeostasis in response to stresses and infections. p53 is tightly regulated by the MDM2 E3 ubiquitin ligase. The p53-MDM2 pathway has co-evolved, with MDM2 remaining largely conserved while the TP53 gene morphed into various isoforms. Studies on pre-vertebrate ancestral homologues revealed the transition from an environmentally-induced mechanism activating p53 to a tightly regulated system involving cell signaling. The evolution of this mechanism depends on structural changes in the interacting protein motifs. Elephants such as Loxodonta africana constitute ideal models to investigate this co-evolution as they are large and long-living as well as having 20 copies of TP53 isoformic sequences expressing a variety of BOX-I MDM2-binding motifs. Collectively, these isoforms would enhance sensitivity to cellular stresses, such as DNA damage, presumably accounting for strong cancer defenses and other adaptations favouring healthy ageing. Here we investigate the molecular evolution of the p53-MDM2 system by combining in silico modelling and in vitro assays to explore structural and functional aspects of p53 isoforms retaining the MDM2 interaction while forming distinct pools of cell-signalling. The methodology used demonstrates, for the first time, that in silico docking simulations can be used to explore functional aspects of elephant p53 isoforms. Our observations elucidate structural and mechanistic aspects of p53 regulation, facilitate understanding of complex cell signalling and suggest testable hypotheses of p53 evolution referencing Peto’s Paradox.
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