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

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 conserve...

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Autores: Padariya, Monikaben|||0000-0002-9132-8620, Jooste, Mia-Lyn, Hupp, Ted, Fåhraeus, Robin|||0000-0003-0402-8492, Vojtesek, Borek|||0000-0001-6194-3705, Vollrath, Fritz|||0000-0003-3484-9005, Kalathiya, Umesh|||0000-0001-7757-6962, Karakostis, Konstantinos|||0000-0003-1122-7860
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:270491
Acceso en línea:https://ddd.uab.cat/record/270491
https://dx.doi.org/urn:doi:10.1093/molbev/msac149
Access Level:acceso abierto
Palabra clave:Structural variations
Model
P53 retrogenes
Molecular evolution
Loxodonta africana
Lifespan
Peto's Paradox
Intrinsic specificity
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spelling The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and CancerPadariya, Monikaben|||0000-0002-9132-8620Jooste, Mia-LynHupp, TedFåhraeus, Robin|||0000-0003-0402-8492Vojtesek, Borek|||0000-0001-6194-3705Vollrath, Fritz|||0000-0003-3484-9005Kalathiya, Umesh|||0000-0001-7757-6962Karakostis, Konstantinos|||0000-0003-1122-7860Structural variationsModelP53 retrogenesMolecular evolutionLoxodonta africanaLifespanPeto's ParadoxIntrinsic specificityThe 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. 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/270491https://dx.doi.org/urn:doi:10.1093/molbev/msac149reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest 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.https://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2704912026-06-06T12:50:31Z
dc.title.none.fl_str_mv The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
title The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
spellingShingle The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
Padariya, Monikaben|||0000-0002-9132-8620
Structural variations
Model
P53 retrogenes
Molecular evolution
Loxodonta africana
Lifespan
Peto's Paradox
Intrinsic specificity
title_short The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
title_full The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
title_fullStr The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
title_full_unstemmed The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
title_sort The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
dc.creator.none.fl_str_mv Padariya, Monikaben|||0000-0002-9132-8620
Jooste, Mia-Lyn
Hupp, Ted
Fåhraeus, Robin|||0000-0003-0402-8492
Vojtesek, Borek|||0000-0001-6194-3705
Vollrath, Fritz|||0000-0003-3484-9005
Kalathiya, Umesh|||0000-0001-7757-6962
Karakostis, Konstantinos|||0000-0003-1122-7860
author Padariya, Monikaben|||0000-0002-9132-8620
author_facet Padariya, Monikaben|||0000-0002-9132-8620
Jooste, Mia-Lyn
Hupp, Ted
Fåhraeus, Robin|||0000-0003-0402-8492
Vojtesek, Borek|||0000-0001-6194-3705
Vollrath, Fritz|||0000-0003-3484-9005
Kalathiya, Umesh|||0000-0001-7757-6962
Karakostis, Konstantinos|||0000-0003-1122-7860
author_role author
author2 Jooste, Mia-Lyn
Hupp, Ted
Fåhraeus, Robin|||0000-0003-0402-8492
Vojtesek, Borek|||0000-0001-6194-3705
Vollrath, Fritz|||0000-0003-3484-9005
Kalathiya, Umesh|||0000-0001-7757-6962
Karakostis, Konstantinos|||0000-0003-1122-7860
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Structural variations
Model
P53 retrogenes
Molecular evolution
Loxodonta africana
Lifespan
Peto's Paradox
Intrinsic specificity
topic Structural variations
Model
P53 retrogenes
Molecular evolution
Loxodonta africana
Lifespan
Peto's Paradox
Intrinsic specificity
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.
publishDate 2022
dc.date.none.fl_str_mv 2
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/270491
https://dx.doi.org/urn:doi:10.1093/molbev/msac149
url https://ddd.uab.cat/record/270491
https://dx.doi.org/urn:doi:10.1093/molbev/msac149
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
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