The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
35792674
PubMed Central
PMC9279639
DOI
10.1093/molbev/msac149
PII: 6632613
Knihovny.cz E-resources
- Keywords
- Loxodonta africana, Peto’s Paradox, intrinsic specificity, lifespan, model, molecular evolution, p53 retrogenes, structural variations,
- MeSH
- Genes, p53 MeSH
- Tumor Suppressor Protein p53 genetics metabolism MeSH
- Neoplasms * genetics MeSH
- Protein Isoforms genetics metabolism MeSH
- Proto-Oncogene Proteins c-mdm2 genetics metabolism MeSH
- Elephants * genetics metabolism MeSH
- Ubiquitination MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Tumor Suppressor Protein p53 MeSH
- Protein Isoforms MeSH
- Proto-Oncogene Proteins c-mdm2 MeSH
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.
Department of Medical Biosciences Umeå University Umeå Sweden
Department of Zoology Zoology Research and Administration Building University of Oxford Oxford UK
Inserm UMRS1131 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis Paris France
Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona Bellaterra Spain
Institute of Genetics and Cancer University of Edinburgh Edinburgh UK
International Centre for Cancer Vaccine Science University of Gdansk ul Kładki 24 Gdansk Poland
Research Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic
Save the Elephants Marula Manor Marula Lane Karen P O Box 54667 Nairobi Kenya
See more in PubMed
Abegglen LM, Caulin AF, Chan A, Lee K, Robinson R, Campbell MS, Kiso WK, Schmitt DL, Waddell PJ, Bhaskara S, et al. 2015. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA 314:1850–1860. PubMed PMC
Allen MA, Andrysik Z, Dengler VL, Mellert HS, Guarnieri A, Freeman JA, Sullivan KD, Galbraith MD, Luo X, Kraus WL, et al. 2014. Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms. Elife 3:e02200. PubMed PMC
Anbarasan T, Bourdon JC. 2019. The emerging landscape of P53 isoforms in physiology, cancer and degenerative diseases. Int J Mol Sci. 20:6257. PubMed PMC
Barreira SN, Nguyen AD, Fredriksen MT, Wolfsberg TG, Moreland RT, Baxevanis AD. 2021. Aniprotdb: a collection of consistently generated metazoan proteomes for comparative genomics studies. Mol Biol Evol. 38:4628–4633. PubMed PMC
Bartas M, Brazda V, Cerven J, Pecinka P. 2019. Characterization of P53 family homologs in evolutionary remote branches of Holozoa. Int J Mol Sci. 21:6. PubMed PMC
Bartas M, Brazda V, Volna A, Cerven J, Pecinka P, Zawacka-Pankau JE. 2021. The changes in the P53 protein across the animal kingdom point to its involvement in longevity. Int J Mol Sci. 22:8512. PubMed PMC
Beck J, Turnquist C, Horikawa I, Harris C. 2020. Targeting cellular senescence in cancer and aging: roles of P53 and its isoforms. Carcinogenesis 41:1017–1029. PubMed PMC
Belyi VA, Ak P, Markert E, Wang H, Hu W, Puzio-Kuter A, Levine AJ. 2010. The origins and evolution of the P53 family of genes. Cold Spring Harb Perspect Biol. 2:a001198. PubMed PMC
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. 2000. The protein data bank. Nucleic Acids Res. 28:235–242. PubMed PMC
Biscotti MA, Barucca M, Carducci F, Forconi M, Canapa A. 2019. The p53 gene family in vertebrates: evolutionary considerations. J Exp Zool B Mol Dev Evol. 332:171–178. PubMed
Bourdon JC, Deguin-Chambon V, Lelong JC, Dessen P, May P, Debuire B, May E. 1997. Further characterisation of the P53 responsive element—identification of new candidate genes for trans-activation by P53. Oncogene 14:85–94. PubMed
Bourdon JC, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP, Saville MK, Lane DP. 2005. P53 isoforms can regulate P53 transcriptional activity. Genes Dev. 19:2122–2137. PubMed PMC
Breton Y, Barat C, Tremblay MJ. 2021. The balance between p53 isoforms modulates the efficiency of HIV-1 infection in macrophages. J Virol. 95:e0118821. PubMed PMC
Brooks BR, Brooks CL 3rd, Mackerell AD Jr., Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, et al. 2009. CHARMM: the biomolecular simulation program. J Comput Chem. 30:1545–1614. PubMed PMC
Brown CJ, Johnson AK, Daughdrill GW. 2010. Comparing models of evolution for ordered and disordered proteins. Mol Biol Evol. 27:609–621. PubMed PMC
Buyukpinarbasili N, Gucin Z, Ersoy YE, Ilbak A, Kadioglu H, Muslumanoglu M. 2016. P53 expression and relationship with MDM2 amplification in breast carcinomas. Ann Diagn Pathol. 21:29–34. PubMed
Callier V. 2019. Core concept: solving Peto's paradox to better understand cancer. Proc Natl Acad Sci U S A. 116:1825–1828. PubMed PMC
Carlsen L, El-Deiry WS. 2021. Differential p53-mediated cellular responses to DNA-damaging therapeutic agents. Int J Mol Sci. 22:11828. PubMed PMC
Chen J. 2016. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb Perspect Med. 6:a026104. PubMed PMC
Chen L, Liu S, Tao Y. 2020. Regulating tumor suppressor genes: post-translational modifications. Signal Transduct Target Ther. 5:90. PubMed PMC
Chen J, Ng SM, Chang C, Zhang Z, Bourdon JC, Lane DP, Peng J. 2009. P53 isoform delta113p53 is a p53 target gene that antagonizes P53 apoptotic activity via BclxL activation in zebrafish. Genes Dev. 23:278–290. PubMed PMC
Chene P. 2003. Inhibiting the p53–MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer. 3:102–109. PubMed
Chusyd DE, Ackermans NL, Austad SN, Hof PR, Mielke MM, Sherwood CC, Allison DB. 2021. Aging: what we can learn from elephants. Front Aging. 2:726714. PubMed PMC
Coffill CR, Lee AP, Siau JW, Chee SM, Joseph TL, Tan YS, Madhumalar A, Tay BH, Brenner S, Verma CS, et al. 2016. The p53–Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans. Genes Dev. 30:281–292. PubMed PMC
Cortez D, Marin R, Toledo-Flores D, Froidevaux L, Liechti A, Waters PD, Grutzner F, Kaessmann H. 2014. Origins and functional evolution of Y chromosomes across mammals. Nature 508:488–493. PubMed
Donehower LA. 2009. Using mice to examine P53 functions in cancer, aging, and longevity. Cold Spring Harb Perspect Biol. 1:a001081. PubMed PMC
Duffy MJ, Synnott NC, O'Grady S, Crown J. 2020. Targeting p53 for the treatment of cancer. Semin Cancer Biol. 79:58–67. PubMed
Edwards KL, Miller MA, Siegal-Willott J, Brown JL. 2020. Serum health biomarkers in African and Asian elephants: value ranges and clinical values indicative of the immune response. Animals (Basel) 10:1756. PubMed PMC
Fahraeus R, Olivares-Illana V. 2014. MDM2's social network. Oncogene 33:4365–4376. PubMed
Farre X, Molina R, Barteri F, Timmers P, Joshi PK, Oliva B, Acosta S, Esteve-Altava B, Navarro A, Muntane G. 2021. Comparative analysis of mammal genomes unveils key genomic variability for human life span. Mol Biol Evol. 38:4948–4961. PubMed PMC
Feng Z, Lin M, Wu R. 2011. The regulation of aging and longevity: a new and complex role of p53. Genes Cancer 2:443–452. PubMed PMC
Fischer M. 2019. Conservation and divergence of the p53 gene regulatory network between mice and humans. Oncogene 38:4095–4109. PubMed PMC
Fujita K. 2019. P53 isoforms in cellular senescence- and ageing-associated biological and physiological functions. Int J Mol Sci. 20:6023. PubMed PMC
Gajjar M, Candeias MM, Malbert-Colas L, Mazars A, Fujita J, Olivares-Illana V, Fahraeus R. 2012. The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for P53 activation following DNA damage. Cancer Cell 21:25–35. PubMed
Ganguly D, Chen J. 2015. Modulation of the disordered conformational ensembles of the P53 transactivation domain by cancer-associated mutations. PLoS Comput Biol. 11:e1004247. PubMed PMC
Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM, Weill JC, Blasco MA, Serrano M. 2002. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 21:6225–6235. PubMed PMC
Gaughran SJ, Pless E, Stearns SC. 2016. How elephants beat cancer. Elife 5:e21864. PubMed PMC
Haronikova L, Olivares-Illana V, Wang L, Karakostis K, Chen S, Fahraeus R. 2019. The p53 mRNA: an integral part of the cellular stress response. Nucleic Acids Res. 47:3257–3271. PubMed PMC
Haupt S, Haupt Y. 2017. P53 at the start of the 21st century: lessons from elephants. F1000Res 6:2041. PubMed PMC
Hendler A, Akiva E, Sandhu M, Goldberg D, Arbely E, Jackson CJ, Aharoni A. 2021. Human SIRT1 multispecificity is modulated by active-site vicinity substitutions during natural evolution. Mol Biol Evol. 38:545–556. PubMed PMC
Hientz K, Mohr A, Bhakta-Guha D, Efferth T. 2017. The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget 8:8921–8946. PubMed PMC
Hsiue EH, Wright KM, Douglass J, Hwang MS, Mog BJ, Pearlman AH, Paul S, DiNapoli SR, Konig MF, Wang Q, et al. 2021. Targeting a neoantigen derived from a common TP53 mutation. Science 371:eabc8697. PubMed PMC
Joerger AC, Wilcken R, Andreeva A. 2014. Tracing the evolution of the p53 tetramerization domain. Structure 22:1301–1310. PubMed PMC
Karagiannakos A, Adamaki M, Tsintarakis A, Vojtesek B, Fåhraeus R, Zoumpourlis V, Karakostis K. 2022. Targeting oncogenic pathways in the era of personalized oncology: a systemic analysis reveals highly mutated signaling pathways in cancer patients and potential therapeutic targets. Cancers 14:664. PubMed PMC
Karakostis K, Fahraeus R. 2019. Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures. BMC Cancer 19:915. PubMed PMC
Karakostis K, Ponnuswamy A, Fusee LT, Bailly X, Laguerre L, Worall E, Vojtesek B, Nylander K, Fahraeus R. 2016. P53 mRNA and p53 protein structures have evolved independently to interact with MDM2. Mol Biol Evol. 33:1280–1292. PubMed
Karakostis K, Vadivel Gnanasundram S, Lopez I, Thermou A, Wang L, Nylander K, Olivares-Illana V, Fahraeus R. 2019. A single synonymous mutation determines the phosphorylation and stability of the nascent protein. J Mol Cell Biol. 11:187–199. PubMed PMC
Keane M, Semeiks J, Webb AE, Li YI, Quesada V, Craig T, Madsen LB, van Dam S, Brawand D, Marques PI, et al. 2015. Insights into the evolution of longevity from the bowhead whale genome. Cell Rep. 10:112–122. PubMed PMC
Khoury MP, Bourdon JC. 2011. P53 isoforms: an intracellular microprocessor? Genes Cancer 2:453–465. PubMed PMC
Klein C, Vassilev LT. 2004. Targeting the p53–MDM2 interaction to treat cancer. Br J Cancer. 91:1415–1419. PubMed PMC
Kubbutat MH, Jones SN, Vousden KH. 1997. Regulation of P53 stability By Mdm2. Nature 387:299–303. PubMed
Kubbutat MH, Ludwig RL, Ashcroft M, Vousden KH. 1998. Regulation of Mdm2-directed degradation by the C terminus of p53. Mol Cell Biol. 18:5690–5698. PubMed PMC
Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP. 1996. Structure of the MDM2 oncoprotein bound to the P53 tumor suppressor transactivation domain. Science 274:948–953. PubMed
Labute P. 2008. The generalized born/volume integral implicit solvent model: estimation of the free energy of hydration using london dispersion instead of atomic surface area. J Comput Chem. 29:1693–1698. PubMed
Lai CW, Xie C, Raufman JP, Xie G. 2022. Targeting post-translational regulation of p53 in colorectal cancer by exploiting vulnerabilities in the p53–MDM2 axis. Cancers (Basel) 14:219. PubMed PMC
Lane D, Levine A. 2010. P53 research: the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol. 2:a000893. PubMed PMC
Levandowski CB, Jones T, Gruca M, Ramamoorthy S, Dowell RD, Taatjes DJ. 2021. The Delta40p53 isoform inhibits p53-dependent eRNA transcription and enables regulation by signal-specific transcription factors during p53 activation. PLoS Biol. 19:e3001364. PubMed PMC
Levine AJ. 2020. P53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer. 20:471–480. PubMed
Liu Y, Tavana O, Gu W. 2019. P53 modifications: exquisite decorations of the powerful guardian. J Mol Cell Biol. 11:564–577. PubMed PMC
Logotheti S, Michalopoulos I, Sideridou M, Daskalos A, Kossida S, Spandidos DA, Field JK, Vojtesek B, Liloglou T, Gorgoulis V, et al. 2010. Sp1 binds to the external promoter of the p73 gene and induces the expression of TAp73gamma in lung cancer. FEBS J. 277:3014–3027. PubMed
Lu WJ, Amatruda JF, Abrams JM. 2009. P53 ancestry: gazing through an evolutionary lens. Nat Rev Cancer. 9:758–762. PubMed
Lynsdale CL, Mumby HS, Hayward AD, Mar KU, Lummaa V. 2017. Parasite-associated mortality in a long-lived mammal: variation with host age, sex, and reproduction. Ecol Evol. 7:10904–10915. PubMed PMC
Mantovani F, Collavin L, Del Sal G. 2019. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 26:199–212. PubMed PMC
Marcel V, Dichtel-Danjoy ML, Sagne C, Hafsi H, Ma D, Ortiz-Cuaran S, Olivier M, Hall J, Mollereau B, Hainaut P, et al. 2011. Biological functions of p53 isoforms through evolution: lessons from animal and cellular models. Cell Death Differ. 18:1815–1824. PubMed PMC
Marcel V, Perrier S, Aoubala M, Ageorges S, Groves MJ, Diot A, Fernandes K, Tauro S, Bourdon JC. 2010. Delta160p53 is a novel N-terminal p53 isoform encoded by Delta133p53 transcript. FEBS Lett. 584:4463–4468. PubMed
Marcel V, Van Long FN, Diaz JJ. 2018. 40 years of research put P53 in translation. Cancers (Basel) 10:152. PubMed PMC
Meek DW, Anderson CW. 2009. Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol. 1:a000950. PubMed PMC
Mehta S, Campbell H, Drummond CJ, Li K, Murray K, Slatter T, Bourdon JC, Braithwaite AW. 2021. Adaptive homeostasis and the P53 isoform network. EMBO Rep. 22:e53085. PubMed PMC
Moding EJ, Min HD, Castle KD, Ali M, Woodlief L, Williams N, Ma Y, Kim Y, Lee CL, Kirsch DG. 2016. An extra copy of P53 suppresses development of spontaneous Kras-driven but not radiation-induced cancer. JCI Insight. 1:e86698. PubMed PMC
Moll UM, Petrenko O. 2003. The MDM2–p53 interaction. Mol Cancer Res. 1:1001–1008. PubMed
Naski N, Gajjar M, Bourougaa K, Malbert-Colas L, Fahraeus R, Candeias MM. 2009. The p53 mRNA–Mdm2 interaction. Cell Cycle 8:31–34. PubMed
Nguyen TT, Grimm SA, Bushel PR, Li J, Li Y, Bennett BD, Lavender CA, Ward JM, Fargo DC, Anderson CW, et al. 2018. Revealing a human p53 universe. Nucleic Acids Res. 46:8153–8167. PubMed PMC
Ota A, Nakao H, Sawada Y, Karnan S, Wahiduzzaman M, Inoue T, Kobayashi Y, Yamamoto T, Ishii N, Ohashi T, et al. 2017. Delta40p53alpha suppresses tumor cell proliferation and induces cellular senescence in hepatocellular carcinoma cells. J Cell Sci. 130:614–625. PubMed PMC
Padariya M, Kote S, Mayordomo M, Dapic I, Alfaro J, Hupp T, Fahraeus R, Kalathiya U. 2021. Structural determinants of peptide-dependent TAP1–TAP2 transit passage targeted by viral proteins and altered by cancer-associated mutations. Comput Struct Biotechnol J. 19:5072–5091. PubMed PMC
Pant V, Xiong S, Jackson JG, Post SM, Abbas HA, Quintas-Cardama A, Hamir AN, Lozano G. 2013. The p53–Mdm2 feedback loop protects against DNA damage by inhibiting P53 activity but is dispensable for P53 stability, development, and longevity. Genes Dev. 27:1857–1867. PubMed PMC
Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M. 2007. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 28:622–629. PubMed
Picksley SM, Vojtesek B, Sparks A, Lane DP. 1994. Immunochemical analysis of the interaction of P53 with MDM2; –fine mapping of the MDM2 binding site on P53 using synthetic peptides. Oncogene 9:2523–2529. PubMed
Reddy PC, Sinha I, Kelkar A, Habib F, Pradhan SJ, Sukumar R, Galande S. 2015. Comparative sequence analyses of genome and transcriptome reveal novel transcripts and variants in the Asian elephant elephas maximus. J Biosci. 40:891–907. PubMed
Rozan LM, El-Deiry WS. 2007. P53 downstream target genes and tumor suppression: a classical view in evolution. Cell Death Differ. 14:3–9. PubMed
Rutkowski R, Hofmann K, Gartner A. 2010. Phylogeny and function of the invertebrate P53 superfamily. Cold Spring Harb Perspect Biol. 2:a001131. PubMed PMC
Salomao N, Karakostis K, Hupp T, Vollrath F, Vojtesek B, Fahraeus R. 2021. What do we need to know and understand about p53 to improve its clinical value? J Pathol. 254:443–453. PubMed
Sharma Y, Miladi M, Dukare S, Boulay K, Caudron-Herger M, Gross M, Backofen R, Diederichs S. 2019. A pan-cancer analysis of synonymous mutations. Nat Commun. 10:2569. PubMed PMC
Siau JW, Coffill CR, Zhang WV, Tan YS, Hundt J, Lane D, Verma C, Ghadessy F. 2016. Functional characterization of p53 pathway components in the ancient metazoan trichoplax adhaerens. Sci Rep. 6:33972. PubMed PMC
Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Soding J, et al. 2011. Fast, scalable generation of high-quality protein multiple sequence alignments using clustal omega. Mol Syst Biol. 7:539. PubMed PMC
Somarelli JA, Boddy AM, Gardner HL, DeWitt SB, Tuohy J, Megquier K, Sheth MU, Hsu SD, Thorne JL, London CA, et al. 2020. Improving cancer drug discovery by studying cancer across the tree of life. Mol Biol Evol. 37:11–17. PubMed PMC
Somarelli JA, Gardner H, Cannataro VL, Gunady EF, Boddy AM, Johnson NA, Fisk JN, Gaffney SG, Chuang JH, Li S, et al. 2020. Molecular biology and evolution of cancer: from discovery to action. Mol Biol Evol. 37:320–326. PubMed PMC
Sonkin D. 2015. Expression signature based on TP53 target genes doesn't predict response To TP53–MDM2 inhibitor in wild type TP53 tumors. Elife 4:e10279. PubMed PMC
Stakyte K, Rotheneder M, Lammens K, Bartho JD, Gradler U, Fuchss T, Pehl U, Alt A, van de Logt E, Hopfner KP. 2021. Molecular basis of human ATM kinase inhibition. Nat Struct Mol Biol. 28:789–798. PubMed
Sulak M, Fong L, Mika K, Chigurupati S, Yon L, Mongan NP, Emes RD, Lynch VJ. 2016. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. Elife 5:e11994. PubMed PMC
Tejada-Martinez D, Avelar RA, Lopes I, Zhang B, Novoa G, de Magalhaes JP, Trizzino M. 2022. Positive selection and enhancer evolution shaped lifespan and body mass in great apes. Mol Biol Evol. 39:msab369. PubMed PMC
Thirion A, Rouanet P, Thezenas S, Detournay D, Grenier J, Lopez-Crapez E. 2002. Interest of investigating p53 status in breast cancer by four different methods. Oncol Rep. 9:1167–1172. PubMed
Tollis M, Boddy AM, Maley CC. 2017. Peto's paradox: how has evolution solved the problem of cancer prevention? BMC Biol. 15:60. PubMed PMC
Tollis M, Ferris E, Campbell MS, Harris VK, Rupp SM, Harrison TM, Kiso WK, Schmitt DL, Garner MM, Aktipis CA, et al. 2021. Elephant genomes reveal accelerated evolution in mechanisms underlying disease defenses. Mol Biol Evol. 38:3606–3620. PubMed PMC
Tollis M, Robbins J, Webb AE, Kuderna LFK, Caulin AF, Garcia JD, Berube M, Pourmand N, Marques-Bonet T, O'Connell MJ, et al. 2019. Return to the sea, get huge, beat cancer: an analysis of cetacean genomes including an assembly for the humpback whale (Megaptera novaeangliae). Mol Biol Evol. 36:1746–1763. PubMed PMC
Tollis M, Schneider-Utaka AK, Maley CC. 2020. The evolution of human cancer gene duplications across mammals. Mol Biol Evol. 37:2875–2886. PubMed PMC
Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, et al. 2002. P53 mutant mice that display early ageing-associated phenotypes. Nature 415:45–53. PubMed
Vazquez JM, Sulak M, Chigurupati S, Lynch VJ. 2018. A zombie LIF gene in elephants is upregulated by TP53 to induce apoptosis in response to DNA damage. Cell Rep. 24:1765–1776. PubMed
Vilar S, Cozza G, Moro S. 2008. Medicinal chemistry and the molecular operating environment (MOE): application of QSAR and molecular docking to drug discovery. Curr Top Med Chem. 8:1555–1572. PubMed
Wallace M, Worrall E, Pettersson S, Hupp TR, Ball KL. 2006. Dual-site regulation of MDM2 E3-ubiquitin ligase activity. Mol Cell. 23:251–263. PubMed
Wang T, Zeng J, Lowe CB, Sellers RG, Salama SR, Yang M, Burgess SM, Brachmann RK, Haussler D. 2007. Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53. Proc Natl Acad Sci U S A. 104:18613–18618. PubMed PMC
Wasylyk C, Salvi R, Argentini M, Dureuil C, Delumeau I, Abecassis J, Debussche L, Wasylyk B. 1999. P53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with P53. Oncogene 18:1921–1934. PubMed
Wheeler LC, Harms MJ. 2021. Were ancestral proteins less specific? Mol Biol Evol. 38:2227–2239. PubMed PMC
Wu D, Prives C. 2018. Relevance of the p53–MDM2 axis to aging. Cell Death Differ. 25:169–179. PubMed PMC
Yang C, Lou G, Jin WL. 2021. The arsenal of TP53 mutants therapies: neoantigens and bispecific antibodies. Signal Transduct Target Ther. 6:219. PubMed PMC
Yim HS, Cho YS, Guang X, Kang SG, Jeong JY, Cha SS, Oh HM, Lee JH, Yang EC, Kwon KK, et al. 2014. Minke whale genome and aquatic adaptation in cetaceans. Nat Genet. 46:88–92. PubMed PMC
Zhan YA, Wu H, Powell AT, Daughdrill GW, Ytreberg FM. 2013. Impact of The K24N mutation on the transactivation domain of P53 and its binding to murine double-minute clone 2. Proteins 81:1738–1747. PubMed PMC
Zhang YX, Pan WY, Chen J. 2019. P53 and its isoforms in DNA double-stranded break repair. J Zhejiang Univ Sci B. 20:457–466. PubMed PMC
Zhao Y, Wu L, Yue X, Zhang C, Wang J, Li J, Sun X, Zhu Y, Feng Z, Hu W. 2018. A polymorphism in the tumor suppressor P53 affects aging and longevity in mouse models. Elife 7 e34701. PubMed PMC
Thermal stress, p53 structures and learning from elephants