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...
| Authors: | ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Publication date: | 2022 |
| Country: | España |
| Institution: | Universitat Autònoma de Barcelona |
| Repository: | Dipòsit Digital de Documents de la UAB |
| Language: | English |
| OAI Identifier: | oai:ddd.uab.cat:270491 |
| Online Access: | https://ddd.uab.cat/record/270491 https://dx.doi.org/urn:doi:10.1093/molbev/msac149 |
| Access Level: | Open access |
| Keyword: | Structural variations Model P53 retrogenes Molecular evolution Loxodonta africana Lifespan Peto's Paradox Intrinsic specificity |
| _version_ | 1878733089833746432 |
|---|---|
| author | Padariya, Monikaben|||0000-0002-9132-8620 |
| 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 |
| author_browse | Fåhraeus, Robin|||0000-0003-0402-8492 Hupp, Ted Jooste, Mia-Lyn Kalathiya, Umesh|||0000-0001-7757-6962 Karakostis, Konstantinos|||0000-0003-1122-7860 Padariya, Monikaben|||0000-0002-9132-8620 Vojtesek, Borek|||0000-0001-6194-3705 Vollrath, Fritz|||0000-0003-3484-9005 |
| 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 |
| collection | Dipòsit Digital de Documents de la UAB |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_4fe387b242ccc2d6d3ffecfa3d0b99e2 |
| institution | Universitat Autònoma de Barcelona |
| instname_str | Universitat Autònoma de Barcelona |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:ddd.uab.cat:270491 |
| publishDate | 2022 |
| publishDateSort | 2022 |
| reponame_str | Dipòsit Digital de Documents de la UAB |
| spelling | The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer 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 Structural variations Model P53 retrogenes Molecular evolution Loxodonta africana Lifespan Peto's Paradox Intrinsic specificity 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. https://ddd.uab.cat/record/270491 https://dx.doi.org/urn:doi:10.1093/molbev/msac149 |
| 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 | 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_short | 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 |
| topic | Structural variations Model P53 retrogenes Molecular evolution Loxodonta africana Lifespan Peto's Paradox Intrinsic specificity |
| topic_facet | Structural variations Model P53 retrogenes Molecular evolution Loxodonta africana Lifespan Peto's Paradox Intrinsic specificity |
| url | https://ddd.uab.cat/record/270491 https://dx.doi.org/urn:doi:10.1093/molbev/msac149 |