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Cited by 33Cancer-related Molecular PathwaysDevelopmental Biology and Gene RegulationHeat shock proteins research

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

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Padariya, Monikaben, Jooste, Mia-Lyn, Hupp, Ted, Fåhraeus, Robin, Vojtesek, Borek, Vollrath, Fritz, Kalathiya, Umesh, Karakostis, Konstantinos·2022·Molecular Biology and Evolution
DOI 10.1093/molbev/msac149PMC PMC9279639
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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.

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  • Elephants possess at least 20 copies of the gene TP5, which prevents apoptosis, or cell death, and protects elephants from cancer.

    “elephants possess at least 20 copies of the gene TP5, which prevents apoptosis, or cell death, and protects elephants from cancer (Abegglen et al., 2015; Chusyd et al., 2021; Padariya et al., 2022; Sulak et al., 2016).”

    From Do elephants really never forget? What we know about elephant memory and a call for further investigation (2025) · cites this paper as Padariya et al., 2022

    The Introduction reports 20 copies of TP53—not “TP5”—and links them to cancer resistance. But the Discussion (Structural Variations on the p53–MDM2 Interface; page unavailable) says elephant p53 retrogenes might enhance the induction of apoptosis, contrary to the claim that they prevent it. (LLM, conf=0.88)

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  • Humans possess only one copy of the gene TP5.

    “In comparison, humans possess only one copy (Abegglen et al., 2015; Chusyd et al., 2021; Padariya et al., 2022; Sulak et al., 2016).”

    From Do elephants really never forget? What we know about elephant memory and a call for further investigation (2025) · cites this paper as Padariya et al., 2022

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Authors
Padariya, M., Jooste, M.-L., Hupp, T., Fåhraeus, R., Vojtesek, B., Vollrath, F., Kalathiya, U., & Karakostis, K.
Affiliations
  • University of Gdańsk (PL)
  • Institute of Genetics and Cancer (GB)
  • International Centre for Cancer Vaccine Science, University of Gdansk , ul. Kładki 24 , Gdansk, Poland
  • Masaryk Memorial Cancer Institute (CZ)
  • Save the Elephants (KE)
  • Universitat Autònoma de Barcelona (ES)
Corresponding author
  • Kalathiya, Umesh
  • Karakostis, Konstantinos
ORCID
Venue
Molecular Biology and Evolution
Publisher
Oxford University Press (OUP)
Published
2022-07-01
Volume
39
Issue
7
ISSN
  • 0737-4038 (ISSN-L)
  • 1537-1719
DOI
10.1093/molbev/msac149
PMC
PMC9279639
OpenAlex
W4283823853
Cited by
33
References
111
Citations by year
2026: 7 · 2025: 8 · 2024: 11 · 2023: 6 · 2022: 1
FWCI
2.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Biology and Evolution (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc)
  • Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, other-oa)
Funders
  • European Commission (CZ.02.1.01/0.0/0.0/16_019/0000868, 00209805, CZ.02.1.01)
  • Institut National de la Santé et de la Recherche Médicale
  • Fundacja na rzecz Nauki Polskiej (MAB/3/2017)
  • Cancerfonden (160598)
  • Narodowe Centrum Nauki (00209805, 2020/36/C/NZ2/00108)
  • Infrastruktura PL-Grid
  • European Regional Development Fund (02.1.01/0.0/0.0, .02.1.01/0.0/0.0/16_019/0000868, CZ.02, CZ.02.1.01/0.0/0.0/16_019 /0000868, 00209805, CZ.02.1.01, CZ.02.1.01/0.0, MMCI, 00209805, CZ.02.1.01/0.0/0.0, /16_019)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
p53, MDM2, Peto's paradox, Loxodonta africana, protein-protein interaction, DNA damage response, healthy aging
MeSH terms
Animals, Elephants, Neoplasms, Genes, p53, Tumor Suppressor Protein p53, Protein Isoforms, Proto-Oncogene Proteins c-mdm2, Ubiquitination

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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