The p53 tumor suppressor is a transcription factor with roles in cell development, apoptosis, oncogenesis, aging, and homeostasis in response to stresses and infections. p53 is tightly regulated by the MDM2 E3 ubiquitin ligase. The p53-MDM2 pathway has coevolved, with MDM2 remaining largely conserved, whereas the TP53 gene morphed into various isoforms. Studies on prevertebrate ancestral homologs 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 coevolution 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 favoring healthy aging. Here we investigate the molecular evolution of the p53-MDM2 system by combining in silico modeling and in vitro assays to explore structural and functional aspects of p53 isoforms retaining the MDM2 interaction, whereas forming distinct pools of cell signaling. 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 signaling, and suggest testable hypotheses of p53 evolution referencing Peto's Paradox.

Department of Medical Biosciences Umeå University Umeå Sweden

Department of Zoology Zoology Research and Administration Building University of Oxford Oxford UK

Inserm UMRS1131 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis Paris France

Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona Bellaterra Spain

Institute of Genetics and Cancer University of Edinburgh Edinburgh UK

International Centre for Cancer Vaccine Science University of Gdansk ul Kładki 24 Gdansk Poland

Research Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Save the Elephants Marula Manor Marula Lane Karen P O Box 54667 Nairobi Kenya

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Thermal stress, p53 structures and learning from elephants

The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway