The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
Padariya, Monikaben (University of Gdansk. International Centre for Cancer Vaccine Science)
Jooste, Mia-Lyn (University of Edinburgh. Institute of Genetics and Cancer)
Hupp, Ted (University of Edinburgh. Institute of Genetics and Cancer)
Fåhraeus, Robin (Umeå University. Department of Medical Biosciences)
Vojtesek, Borek (Masaryk Memorial Cancer Institute)
Vollrath, Fritz (Save the Elephants Marula Manor)
Kalathiya, Umesh (University of Gdansk. International Centre for Cancer Vaccine Science)
Karakostis, Konstantinos (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")

Date:	2022
Abstract:	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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Structural variations ; Model ; P53 retrogenes ; Molecular evolution ; Loxodonta africana ; Lifespan ; Peto's Paradox ; Intrinsic specificity
Published in:	Molecular biology and evolution, Vol. 39, Issue 7 (July 2022) , art. msac149, ISSN 1537-1719

DOI: 10.1093/molbev/msac149
PMID: 35792674

15 p, 1.1 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles