The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209805%3A_____%2F22%3A00079025" target="_blank" >RIV/00209805:_____/22:00079025 - isvavai.cz</a>
Result on the web
<a href="https://pubmed.ncbi.nlm.nih.gov/35792674/" target="_blank" >https://pubmed.ncbi.nlm.nih.gov/35792674/</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1093/molbev/msac149" target="_blank" >10.1093/molbev/msac149</a>
Alternative languages
Result language
angličtina
Original language name
The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/EF16_019%2F0000868" target="_blank" >EF16_019/0000868: Molecular, cellular and clinical approach to healthy ageing</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
MOLECULAR BIOLOGY AND EVOLUTION
ISSN
0737-4038
e-ISSN
1537-1719
Volume of the periodical
39
Issue of the periodical within the volume
7
Country of publishing house
GB - UNITED KINGDOM
Number of pages
15
Pages from-to
"msac149"
UT code for WoS article
000824994500001
EID of the result in the Scopus database
2-s2.0-85134431076