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image of Human P53 Expression in Yeast: Investigating Its Apoptotic Effects

Abstract

Since its discovery in 1979, the tumor suppressor p53 has been widely studied and expressed in various organisms, including yeast. Yeast has proven to be a very informative model and an effective system for studying the roles and functions of this protein and gene. This review is a compilation of our team's studies involving p53 expression in yeast. These researches investigated certain aspects, essentially the apoptotic function of p53. Our main contribution to the study and understanding of the p53 gene in the yeast context is the confirmation of a negative effect of p53 on cell growth in both and strains, which ultimately led to apoptotic cell death. This involves a high dose of p53 and the NLS signal, which enables p53 to target both the mitochondria and the nucleus. Prior to that, obtaining the whole protein required a cDNA without its UTR. Thus, a yeast model was developed, allowing verification of p53 activity. Cancer mutants and their revertants could thereby be assessed. This has evolved into a real antioxidant/anti-apoptotic molecular screening mechanism. Two primary applications were achieved: testing the co-expression with the thioredoxin 2 gene (TRX2) and assessing the impact of seed extracts. Furthermore, the high yield of yeast P53 production allowed its use in serological cancer diagnosis.

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2026-01-22
2026-01-29

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References

  1. Senturk E. Manfredi J.J. p53 and cell cycle effects after DNA damage. Methods Mol. Biol. 2013 962 49 61 10.1007/978‑1‑62703‑236‑0_4 23150436
    [Google Scholar]
  2. Chen X. Zhang T. Su W. Dou Z. Zhao D. Jin X. Lei H. Wang J. Xie X. Cheng B. Li Q. Zhang H. Di C. Mutant p53 in cancer: From molecular mechanism to therapeutic modulation. Cell Death Dis. 2022 13 11 974 10.1038/s41419‑022‑05408‑1 36400749
    [Google Scholar]
  3. Tornesello M. TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review). Int. J. Mol. Med. 2024 55 1 7 10.3892/ijmm.2024.5448 39450536
    [Google Scholar]
  4. Guha T. Malkin D. Inherited TP53 mutations and the Li–Fraumeni syndrome. Cold Spring Harb. Perspect. Med. 2017 7 4 a026187 10.1101/cshperspect.a026187 28270529
    [Google Scholar]
  5. Danishevich A. Fedorova D. Bodunova N. Makarova M. Byakhova M. Semenova A. Galkin V. Litvinova M. Nikolaev S. Efimova I. Osinin P. Lisitsa T. Khakhina A. Shipulin G. Nasedkina T. Shumilova S. Gusev O. Bilyalov A. Shagimardanova E. Shigapova L. Nemtsova M. Sagaydak O. Woroncow M. Gadzhieva S. Khatkov I. Assessing germline TP53 mutations in cancer patients: Insights into Li-Fraumeni syndrome and genetic testing guidelines. Hered. Cancer Clin. Pract. 2025 23 1 5 10.1186/s13053‑025‑00307‑w 39962599
    [Google Scholar]
  6. Kern S.E. Kinzler K.W. Bruskin A. Jarosz D. Friedman P. Prives C. Vogelstein B. Identification of p53 as a sequence-specific DNA-binding protein. Science 1991 252 5013 1708 1711 10.1126/science.2047879 2047879
    [Google Scholar]
  7. Burns T.F. El-Deiry W.S. The p53 pathway and apoptosis. J. Cell. Physiol. 1999 181 2 231 239 10.1002/(SICI)1097‑4652(199911)181:2<231::AID‑JCP5>3.0.CO;2‑L 10497302
    [Google Scholar]
  8. Bargonetti J. Manfredi J.J. Multiple roles of the tumor suppressor p53. Curr. Opin. Oncol. 2002 14 1 86 91 10.1097/00001622‑200201000‑00015 11790986
    [Google Scholar]
  9. El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell 1993 75 4 817 825 10.1016/0092‑8674(93)90500‑P 8242752
    [Google Scholar]
  10. Chen J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med. 2016 6 3 a026104 10.1101/cshperspect.a026104 26931810
    [Google Scholar]
  11. Mihara M. Erster S. Zaika A. Petrenko O. Chittenden T. Pancoska P. Moll U.M. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 2003 11 3 577 590 10.1016/S1097‑2765(03)00050‑9 12667443
    [Google Scholar]
  12. Liu Y. Su Z. Tavana O. Gu W. Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell 2024 42 6 946 967 10.1016/j.ccell.2024.04.009 38729160
    [Google Scholar]
  13. Cervelli T. Galli A. Yeast as a tool to understand the significance of human disease-associated gene variants. Genes 2021 12 9 1303 10.3390/genes12091303 34573285
    [Google Scholar]
  14. Schärer E. lggo, R. Mammalian p53 can function as a transcription factor in yeast. Nucleic Acids Res. 1992 20 7 1539 1545 10.1093/nar/20.7.1539 1579447
    [Google Scholar]
  15. Inga A. Cresta S. Monti P. Aprile A. Scott G. Abbondandolo A. Iggo R. Fronza G. Simple identification of dominant p53 mutants by a yeast functional assay. Carcinogenesis 1997 18 10 2019 2021 10.1093/carcin/18.10.2019 9364015
    [Google Scholar]
  16. Monti P. Bosco B. Gomes S. Saraiva L. Fronza G. Inga A. Yeast as a chassis for developing functional assays to study human p53. J. Vis. Exp. 2019 150 10.3791/59071 31424436
    [Google Scholar]
  17. Sharma V. Monti P. Fronza G. Inga A. Human transcription factors in yeast: The fruitful examples of P53 and NF-кB. FEMS Yeast Res. 2016 16 7 fow083 10.1093/femsyr/fow083 27683095
    [Google Scholar]
  18. Deissler H. Kafka A. Schuster E. Sauer G. Kreienberg R. Zeillinger R. Spectrum of p53 mutations in biopsies from breast cancer patients selected for preoperative chemotherapy analysed by the functional yeast assay to predict therapeutic response. Oncol. Rep. 2004 11 6 1281 1286 10.3892/or.11.6.1281 15138567
    [Google Scholar]
  19. Iggo R. Rudewicz J. Monceau E. Sevenet N. Bergh J. Sjoblom T. Bonnefoi H. Validation of a yeast functional assay for p53 mutations using clonal sequencing. J. Pathol. 2013 231 4 441 448 10.1002/path.4243 23897043
    [Google Scholar]
  20. Guaragnella N. Palermo V. Galli A. Moro L. Mazzoni C. Giannattasio S. The expanding role of yeast in cancer research and diagnosis: Insights into the function of the oncosuppressors p53 and BRCA1/2. FEMS Yeast Res. 2014 14 1 2 16 10.1111/1567‑1364.12094 24103154
    [Google Scholar]
  21. Mokdad-Gargouri R. Belhadj K. Gargouri, A Translational control of human p53 expression in yeast mediated by 5′-UTR-ORF structural interaction. Nucleic Acids Res. 2001 29 5 1222 1227 10.1093/nar/29.5.1222 11222773
    [Google Scholar]
  22. Swiatkowska A. Dutkiewicz M. Zydowicz-Machtel P. Szpotkowska J. Janecki D.M. Ciesiołka J. Translational control in p53 expression: The role of 5′-terminal region of p53 mRNA. Int. J. Mol. Sci. 2019 20 21 5382 10.3390/ijms20215382 31671760
    [Google Scholar]
  23. Koh W.S. Porter J.R. Batchelor E. Tuning of mRNA stability through altering 3′-UTR sequences generates distinct output expression in a synthetic circuit driven by p53 oscillations. Sci. Rep. 2019 9 1 5976 10.1038/s41598‑019‑42509‑y 30979970
    [Google Scholar]
  24. Hadj Amor I.Y. Smaoui K. Chaabène, I.; Mabrouk, I.; Djemal, L.; Elleuch, H.; Allouche, M.; Mokdad-Gargouri, R.; Gargouri, A. Human p53 induces cell death and downregulates thioredoxin expression in Saccharomyces cerevisiae. FEMS Yeast Res. 2008 8 8 1254 1262 10.1111/j.1567‑1364.2008.00445.x 19054132
    [Google Scholar]
  25. Abdelmoula-Souissi S. Delahodde A. Bolotin-Fukuhara M. Gargouri A. Mokdad-Gargouri R. Cellular localization of human p53 expressed in the yeast Saccharomyces cerevisiae: Effect of NLSI deletion. Apoptosis 2011 16 7 746 756 10.1007/s10495‑011‑0607‑z 21553245
    [Google Scholar]
  26. Inga A. Resnick M.A. Novel human p53 mutations that are toxic to yeast can enhance transactivation of specific promoters and reactivate tumor p53 mutants. Oncogene 2001 20 26 3409 3419 10.1038/sj.onc.1204457 11423991
    [Google Scholar]
  27. Mihoubi W. Sahli E. Gargouri A. Amiel C. FTIR spectroscopy of whole cells for the monitoring of yeast apoptosis mediated by p53 over-expression and its suppression by Nigella sativa extracts. PLoS One 2017 12 7 e0180680 10.1371/journal.pone.0180680 28704406
    [Google Scholar]
  28. Bischoff J.R. Casso D. Beach D. Human p53 inhibits growth in Schizosaccharomyces pombe. Mol. Cell. Biol. 1992 12 4 1405 1411 10.1128/mcb.12.4.1405‑1411.1992 1549103
    [Google Scholar]
  29. Fields S. Jang S.K. Presence of a potent transcription activating sequence in the p53 protein. Science 1990 249 4972 1046 1049 10.1126/science.2144363 2144363
    [Google Scholar]
  30. Nigro J.M. Sikorski R. Reed S.I. Vogelstein B. Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae. Mol. Cell. Biol. 1992 12 3 1357 1365 10.1128/mcb.12.3.1357‑1365.1992 1545817
    [Google Scholar]
  31. Abdelmoula-Souissi S. Mabrouk I. Gargouri A. Mokdad-Gargouri R. Expression of the human tumor suppressor p53 induces cell death in Pichia pastoris. FEMS Yeast Res. 2012 12 1 2 8 10.1111/j.1567‑1364.2011.00758.x 22093905
    [Google Scholar]
  32. Abdelmoula-Souissi S. Rekik L. Gargouri A. Mokdad-Gargouri R. High-level expression of human tumour suppressor P53 in the methylotrophic yeast: Pichia pastoris. Protein Expr. Purif. 2007 54 2 283 288 10.1016/j.pep.2007.03.015 17482479
    [Google Scholar]
  33. Macauley-Patrick S. Fazenda M.L. McNeil B. Harvey L.M. Heterologous protein production using the Pichia pastoris expression system. Yeast 2005 22 4 249 270 10.1002/yea.1208 15704221
    [Google Scholar]
  34. Kumar A. Dandekar J.U. Bhat P.J. Fermentative metabolism impedes p53-dependent apoptosis in a Crabtree-positive but not in Crabtree-negative yeast. J. Biosci. 2017 42 4 585 601 10.1007/s12038‑017‑9717‑2 29229877
    [Google Scholar]
  35. Wendisch V.F. Kosec G. Heux S. Brautaset T. Aerobic utilization of methanol for microbial growth and production. Adv. Biochem. Eng. Biotechnol. 2021 180 169 212 10.1007/10_2021_177 34761324
    [Google Scholar]
  36. Wu X. Cai P. Yao L. Zhou Y.J. Genetic tools for metabolic engineering of Pichia pastoris. Engineering Microbiology 2023 3 4 100094 10.1016/j.engmic.2023.100094 39628915
    [Google Scholar]
  37. Hu R. Cui R. Xu Q. Lan D. Wang Y. Controlling specific growth rate for recombinant protein production by pichia pastoris under oxidation stress in fed-batch fermentation. Appl. Biochem. Biotechnol. 2022 194 12 6179 6193 10.1007/s12010‑022‑04022‑3 35900712
    [Google Scholar]
  38. Gan Y. Meng X. Gao C. Song W. Liu L. Chen X. Metabolic engineering strategies for microbial utilization of methanol. Engineering Microbiology 2023 3 3 100081 10.1016/j.engmic.2023.100081 39628934
    [Google Scholar]
  39. Khatri N.K. Hoffmann F. Impact of methanol concentration on secreted protein production in oxygen‐limited cultures of recombinant Pichia pastoris. Biotechnol. Bioeng. 2006 93 5 871 879 10.1002/bit.20773 16320364
    [Google Scholar]
  40. Wang S. Wang Y. Yuan Q. Yang L. Zhao F. Lin Y. Han S. Development of high methanol-tolerance Pichia pastoris based on iterative adaptive laboratory evolution. Green Chem. 2023 25 21 8845 8857 10.1039/D3GC02874G
    [Google Scholar]
  41. Grosfeld E.V. Bidiuk V.A. Mitkevich O.V. Ghazy E.S.M.O. Kushnirov V.V. Alexandrov A.I. A systematic survey of characteristic features of yeast cell death triggered by external factors. J. Fungi 2021 7 11 886 10.3390/jof7110886 34829175
    [Google Scholar]
  42. Liu Z. Yu K. Wu S. Weng X. Luo S. Zeng M. Wang X. Hu X. Comparative lipidomics of methanol induced Pichia pastoris cells at different culture phases uncovers the diversity and variability of lipids. Enzyme Microb. Technol. 2022 160 110090 10.1016/j.enzmictec.2022.110090 35780701
    [Google Scholar]
  43. Zhang W. Bevins M.A. Plantz B.A. Smith L.A. Meagher M.M. Modeling Pichia pastoris growth on methanol and optimizing the production of a recombinant protein, the heavy-chain fragment C of botulinum neurotoxin, serotype A. Biotechnol. Bioeng. 2000 70 1 1 8 10.1002/1097‑0290(20001005)70:1<1::AIDBIT1>3.0.CO;2‑Y 10940857
    [Google Scholar]
  44. Yan H. Liu N. Zhao Z. Zhang X. Xu H. Shao B. Yan W. Expression and purification of human TAT-p53 fusion protein in Pichia pastoris and its influence on HepG2 cell apoptosis. Biotechnol. Lett. 2012 34 7 1217 1223 10.1007/s10529‑012‑0905‑8 22426841
    [Google Scholar]
  45. Yohannes E. Barnhart D.M. Slonczewski J.L. pH-dependent catabolic protein expression during anaerobic growth of Escherichia coli K-12. J. Bacteriol. 2004 186 1 192 199 10.1128/JB.186.1.192‑199.2004 14679238
    [Google Scholar]
  46. Stancik L.M. Stancik D.M. Schmidt B. Barnhart D.M. Yoncheva Y.N. Slonczewski J.L. pH-dependent expression of periplasmic proteins and amino acid catabolism in Escherichia coli. J. Bacteriol. 2002 184 15 4246 4258 10.1128/JB.184.15.4246‑4258.2002 12107143
    [Google Scholar]
  47. Schumacher K. Gelhausen R. Kion-Crosby W. Barquist L. Backofen R. Jung K. Ribosome profiling reveals the fine-tuned response of Escherichia coli to mild and severe acid stress. mSystems 2023 8 6 e01037 23 10.1128/msystems.01037‑23 37909716
    [Google Scholar]
  48. Lee S. Shanti A. Effect of exogenous pH on cell growth of breast cancer cells. Int. J. Mol. Sci. 2021 22 18 9910 10.3390/ijms22189910 34576073
    [Google Scholar]
  49. Iwahashi N. Ikezaki M. Komohara Y. Fujiwara Y. Noguchi T. Nishioka K. Sakai K. Nishio K. Ueda M. Ihara Y. Uchimura K. Ino K. Nishitsuji K. Cytoplasmic p53 aggregates accumulated in p53-mutated cancer correlate with poor prognosis. PNAS Nexus 2022 1 3 pgac128 10.1093/pnasnexus/pgac128 36741442
    [Google Scholar]
  50. Petronilho E.C. Pedrote M.M. Marques M.A. Passos Y.M. Mota M.F. Jakobus B. Sousa G.S. Pereira da Costa F. Felix A.L. Ferretti G.D.S. Almeida F.P. Cordeiro Y. Vieira T.C.R.G. de Oliveira G.A.P. Silva J.L. Phase separation of p53 precedes aggregation and is affected by oncogenic mutations and ligands. Chem. Sci. 2021 12 21 7334 7349 10.1039/D1SC01739J 34163823
    [Google Scholar]
  51. Park S.K. Park S. Pentek C. Liebman S.W. Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets. iScience 2021 24 1 102000 10.1016/j.isci.2020.102000 33490908
    [Google Scholar]
  52. Billant O. Friocourt G. Roux P. Voisset C. p53, a victim of the prion fashion. Cancers 2021 13 2 269 10.3390/cancers13020269 33450819
    [Google Scholar]
  53. Liebman S.W. Derkatch I.L. Park S. Park S.K. Comment on Billant et al. p53, a victim of the prion fashion. Cancers 2021, 13, 269. Cancers 2023 15 1 309 10.3390/cancers15010309 36612305
    [Google Scholar]
  54. Rangel L.P. Costa D.C.F. Vieira T.C.R.G. Silva J.L. The aggregation of mutant p53 produces prion-like properties in cancer. Prion 2014 8 1 75 84 10.4161/pri.27776 24509441
    [Google Scholar]
  55. Kwan K. Castro-Sandoval O. Gaiddon C. Storr T. Inhibition of p53 protein aggregation as a cancer treatment strategy. Curr. Opin. Chem. Biol. 2023 72 102230 10.1016/j.cbpa.2022.102230 36436275
    [Google Scholar]
  56. Mihoubi W. Sahli E. Rezgui F. Dabebi N. Sayehi R. Hassairi H. Masmoudi-Fourati N. Walha K. ben Khadhra, K.; Baklouti, M.; Ghzaiel, I.; Fattouch, S.; Menif, H.; Mokdad-Gargouri, R.; Lizard, G.; Gargouri, A. Whole and purified aqueous extracts of Nigella sativa L. seeds attenuate apoptosis and the overproduction of reactive oxygen species triggered by p53 over-expression in the yeast Saccharomyces cerevisiae. Cells 2022 11 5 869 10.3390/cells11050869 35269491
    [Google Scholar]
  57. Yacoubi-Hadj Amor I. Smaoui K. Belguith H. Djemal L. Dardouri M. Mokdad-Gargouri R. Gargouri A. Selection of cell death‐deficient p53 mutants in Saccharomyces cerevisiae. Yeast 2009 26 8 441 450 10.1002/yea.1677 19579214
    [Google Scholar]
  58. Voordeckers K. De Maeyer D. van der Zande E. Vinces M.D. Meert W. Cloots L. Ryan O. Marchal K. Verstrepen K.J. Identification of a complex genetic network underlyingS accharomyces cerevisiae colony morphology. Mol. Microbiol. 2012 86 1 225 239 10.1111/j.1365‑2958.2012.08192.x 22882838
    [Google Scholar]
  59. Sanford J.D. Jin A. Grois G.A. Zhang Y. A role of cytoplasmic p53 in the regulation of metabolism shown by bat-mimicking p53 NLS mutant mice. Cell Rep. 2023 42 1 111920 10.1016/j.celrep.2022.111920 36640361
    [Google Scholar]
  60. Li W. Li W. Li X. Wang L. Wang Y. Effect of P53 nuclear localization mediated by G3BP1 on ferroptosis in acute liver failure. Apoptosis 2023 28 7-8 1226 1240 10.1007/s10495‑023‑01856‑y 37243773
    [Google Scholar]
  61. Chen F. Kang R. Tang D. Liu J. Ferroptosis: Principles and significance in health and disease. J. Hematol. Oncol. 2024 17 1 41 10.1186/s13045‑024‑01564‑3 38844964
    [Google Scholar]
  62. Lu J. Wu T. Zhang B. Liu S. Song W. Qiao J. Ruan H. Types of nuclear localization signals and mechanisms of protein import into the nucleus. Cell Commun. Signal. 2021 19 1 60 10.1186/s12964‑021‑00741‑y 34022911
    [Google Scholar]
  63. Rius-Pérez S. Pérez S. Toledano M.B. Sastre J. p53 drives necroptosis via downregulation of sulfiredoxin and peroxiredoxin 3. Redox Biol. 2022 56 102423 10.1016/j.redox.2022.102423 36029648
    [Google Scholar]
  64. Barbero-Úriz Ó. Valenti M. Molina M. Fernández-Acero T. Cid V.J. Modeling necroptotic and pyroptotic signaling in Saccharomyces cerevisiae. Biomolecules 2025 15 4 530 10.3390/biom15040530 40305268
    [Google Scholar]
  65. Leão M. Gomes S. Bessa C. Soares J. Raimundo L. Monti P. Fronza G. Pereira C. Saraiva L. Studying p53 family proteins in yeast: Induction of autophagic cell death and modulation by interactors and small molecules. Exp. Cell Res. 2015 330 1 164 177 10.1016/j.yexcr.2014.09.028 25265062
    [Google Scholar]
  66. Carmona-Gutierrez D. Bauer M.A. Zimmermann A. Aguilera A. Austriaco N. Ayscough K. Balzan R. Bar-Nun S. Barrientos A. Belenky P. Blondel M. Braun R.J. Breitenbach M. Burhans W.C. Buettner S. Cavalieri D. Chang M. Cooper K.F. Côrte-Real M. Costa V. Cullin C. Dawes I. Dengjel J. Dickman M.B. Eisenberg T. Fahrenkrog B. Fasel N. Froehlich K-U. Gargouri A. Giannattasio S. Goffrini P. Gourlay C.W. Grant C.M. Greenwood M.T. Guaragnella N. Heger T. Heinisch J. Herker E. Herrmann J.M. Hofer S. Jiménez-Ruiz A. Jungwirth H. Kainz K. Kontoyiannis D.P. Ludovico P. Manon S. Martegani E. Mazzoni C. Megeney L.A. Meisinger C. Nielsen J. Nystroem T. Osiewacz H.D. Outeiro T.F. Park H.O. Pendl T. Petranovic D. Picot S. Polčic P. Powers T. Ramsdale M. Rinnerthaler M. Rockenfeller P. Ruckenstuhl C. Schaffrath R. Segovia M. Severin F.F. Sharon A. Sigrist S.J. Sommer-Ruck C. Sousa M.J. Thevelein J.M. Thevissen K. Titorenko V. Toledano M.B. Tuite M. Voegtle F-N. Westermann B. Winderickx J. Wissing S. Woelfl S. Zhang Z.J. Zhao R.Y. Zhou B. Galluzzi L. Kroemer G. Madeo F. Guidelines and recommendations on yeast cell death nomenclature. Microb. Cell 2018 5 1 4 31 10.15698/mic2018.01.607 29354647
    [Google Scholar]
  67. Coutinho I. Pereira G. Leão M. Gonçalves J. Côrte-Real M. Saraiva L. Differential regulation of p53 function by protein kinase C isoforms revealed by a yeast cell system. FEBS Lett. 2009 583 22 3582 3588 10.1016/j.febslet.2009.10.030 19840791
    [Google Scholar]
  68. Flaman J.M. Frebourg T. Moreau V. Charbonnier F. Martin C. Chappuis P. Sappino A.P. Limacher I.M. Bron L. Benhattar J.A. simple p53 functional assay for screening cell lines, blood, and tumors. Proc. Natl. Acad. Sci. USA 1995 92 9 3963 3967 10.1073/pnas.92.9.3963 7732013
    [Google Scholar]
  69. Leão M. Gomes S. Soares J. Bessa C. Maciel C. Ciribilli Y. Pereira C. Inga A. Saraiva L. Novel simplified yeast-based assays of regulators of p53-MDMX interaction and p53 transcriptional activity. FEBS J. 2013 280 24 6498 6507 10.1111/febs.12552 24119020
    [Google Scholar]
  70. Inga A. Monti P. Fronza G. Darden T. Resnick M.A. p53 mutants exhibiting enhanced transcriptional activation and altered promoter selectivity are revealed using a sensitive, yeast-based functional assay. Oncogene 2001 20 4 501 513 10.1038/sj.onc.1204116 11313981
    [Google Scholar]
  71. Denney A.S. Weems A.D. McMurray M.A. Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast. G3 2021 11 9 jkab230 10.1093/g3journal/jkab230 34544131
    [Google Scholar]
  72. Müntnich L.J. Dutzmann C.M. Großhennig A. Härter V. Keymling M. Mastronuzzi A. Montellier E. Nees J. Palmaers N.E. Penkert J. Pfister S.M. Ripperger T. Schott S. Silchmüller F. Hainaut P. Kratz C.P. Cancer risk in carriers of TP53 germline variants grouped into different functional categories. JNCI Cancer Spectr. 2025 9 1 pkaf008 10.1093/jncics/pkaf008 39873732
    [Google Scholar]
  73. Epstein C.B. Attiyeh E.F. Hobson D.A. Silver A.L. Broach J.R. Levine A.J. p53 mutations isolated in yeast based on loss of transcription factor activity: Similarities and differences from p53 mutations detected in human tumors. Oncogene 1998 16 16 2115 2122 10.1038/sj.onc.1201734 9572492
    [Google Scholar]
  74. Funk J.S. Klimovich M. Drangenstein D. Pielhoop O. Hunold P. Borowek A. Noeparast M. Pavlakis E. Neumann M. Balourdas D.I. Kochhan K. Merle N. Bullwinkel I. Wanzel M. Elmshäuser S. Teply-Szymanski J. Nist A. Procida T. Bartkuhn M. Humpert K. Mernberger M. Savai R. Soussi T. Joerger A.C. Stiewe T. Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations. Nat. Genet. 2025 57 1 140 153 10.1038/s41588‑024‑02039‑4 39774325
    [Google Scholar]
  75. Woo D.K. Poyton R.O. The absence of a mitochondrial genome in rho0 yeast cells extends lifespan independently of retrograde regulation. Exp. Gerontol. 2009 44 6-7 390 397 10.1016/j.exger.2009.03.001 19285548
    [Google Scholar]
  76. Rius-Pérez S. p53 at the crossroad between mitochondrial reactive oxygen species and necroptosis. Free Radic. Biol. Med. 2023 207 183 193 10.1016/j.freeradbiomed.2023.07.022 37481144
    [Google Scholar]
  77. Li J. Huang X. Luo L. Sun J. Guo Q. Yang X. Zhang C. Ni B. The role of p53 in male infertility. Front. Endocrinol. 2024 15 1457985 10.3389/fendo.2024.1457985 39469578
    [Google Scholar]
  78. Nishinaka Y. Masutani H. Nakamura H. Yodoi J. Regulatory roles of thioredoxin in oxidative stress-induced cellular responses. Redox Rep. 2001 6 5 289 295 10.1179/135100001101536427 11778846
    [Google Scholar]
  79. Hirota K. Matsui M. Iwata S. Nishiyama A. Mori K. Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc. Natl. Acad. Sci. USA 1997 94 8 3633 3638 10.1073/pnas.94.8.3633 9108029
    [Google Scholar]
  80. Ueno M. Masutani H. Arai R.J. Yamauchi A. Hirota K. Sakai T. Inamoto T. Yamaoka Y. Yodoi J. Nikaido T. Thioredoxin-dependent redox regulation of p53-mediated p21 activation. J. Biol. Chem. 1999 274 50 35809 35815 10.1074/jbc.274.50.35809 10585464
    [Google Scholar]
  81. Ueno M. Matsutani Y. Nakamura H. Masutani H. Yagi M. Yamashiro H. Kato H. Inamoto T. Yamauchi A. Takahashi R. Yamaoka Y. Yodoi J. Possible association of thioredoxin and p53 in breast cancer. Immunol. Lett. 2000 75 1 15 20 10.1016/S0165‑2478(00)00284‑4 11163861
    [Google Scholar]
  82. Jabbar S. Mathews P. Wang X. Sundaramoorthy P. Chu E. Piryani S.O. Ding S. Shen X. Doan P.L. Kang Y. Thioredoxin-1 regulates self-renewal and differentiation of murine hematopoietic stem cells through p53 tumor suppressor. Exp. Hematol. Oncol. 2022 11 1 83 10.1186/s40164‑022‑00329‑3 36316713
    [Google Scholar]
  83. Moradi M. Karimi J. Khodadadi I. Amiri I. Karami M. Saidijam M. Vatannejad A. Tavilani H. Evaluation of the p53 and Thioredoxin reductase in sperm from asthenozoospermic males in comparison to normozoospermic males. Free Radic. Biol. Med. 2018 116 123 128 10.1016/j.freeradbiomed.2017.12.038 29305108
    [Google Scholar]
  84. Kamoun Y. Mabrouk I. Delahodde A. Boukid F. Yacoubi-Hadj Amor I. Mokdad-Gargouri R. Gargouri A. Overexpression of yeast thioredoxin TRX2 reduces p53-mediated cell death in yeast. Appl. Microbiol. Biotechnol. 2015 99 20 8619 8628 10.1007/s00253‑015‑6886‑5 26264138
    [Google Scholar]
  85. Cunningham G.M. Flores L.C. Roman M.G. Cheng C. Dube S. Allen C. Valentine J.M. Hubbard G.B. Bai Y. Saunders T.L. Ikeno Y. Thioredoxin overexpression in both the cytosol and mitochondria accelerates age-related disease and shortens lifespan in male C57BL/6 mice. Geroscience 2018 40 5-6 453 468 10.1007/s11357‑018‑0039‑6 30121784
    [Google Scholar]
  86. Roman M.G. Flores L.C. Cunningham G.M. Cheng C. Dube S. Allen C. Remmen H.V. Bai Y. Hubbard G.B. Saunders T.L. Ikeno Y. Thioredoxin overexpression in mitochondria showed minimum effects on aging and age-related diseases in male C57BL/6 mice. Aging Pathobiol. Ther. 2020 2 1 20 31 10.31491/APT.2020.03.009 35356005
    [Google Scholar]
  87. Tang H. Kim M. Lee M. Baumann K. Olguin F. He H. Wang Y. Jiang B. Fang S. Zhu J. Wang K. Xia H. Gao Y. Konsker H.B. Fatodu E.A. Quarta M. Blonigan J. Rando T.A. Shrager J.B. Overexpression of thioredoxin‐2 attenuates age‐related muscle loss by suppressing mitochondrial oxidative stress and apoptosis. JCSM Rapid Commun. 2022 5 1 130 145 10.1002/rco2.57 40236683
    [Google Scholar]
  88. Meng L. Song B. Shi X. Duan A. Lu D. Ren Y. Zhang Y. Shou R. Li H. Wang Z. Liu J. Wang Z. Sun X. Overexpression of thioredoxin 1 contributes to neuroprotection through ATM activation and pentose phosphate pathway modulation after traumatic brain injury. Exp. Neurol. 2025 392 115326 10.1016/j.expneurol.2025.115326 40449785
    [Google Scholar]
  89. Hasan A.A. Kalinina E. Tatarskiy V. Shtil A. The thioredoxin system of mammalian cells and its modulators. Biomedicines 2022 10 7 1757 10.3390/biomedicines10071757 35885063
    [Google Scholar]
  90. Raninga P. Kalimutho M. Sinha D. Bain A. Tonissen K. Khanna K.K. Targeting thioredoxin reductase 1 in novel combination therapies in p53 mutant triple negative breast cancer. Ann. Oncol. 2017 28 Suppl. 5 v584 10.1093/annonc/mdx390.035
    [Google Scholar]
  91. Liu Y. Zhao Y. Wei Z. Tao L. Sheng X. Wang S. Chen J. Ruan J. Liu Z. Cao Y. Shan Y. Wang A. Chen W. Lu Y. Targeting thioredoxin system with an organosulfur compound, Diallyl Trisulfide (DATS), attenuates progression and metastasis of triple-negative Breast Cancer (TNBC). Cell. Physiol. Biochem. 2018 50 5 1945 1963 10.1159/000494874 30396169
    [Google Scholar]
  92. Raninga P.V. He Y. Datta K.K. Lu X. Maheshwari U.R. Venkat P. Mayoh C. Gowda H. Kalimutho M. Hooper J.D. Khanna K.K. Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-tumor activity in MYC-high high-grade serous ovarian carcinoma. Mol. Ther. 2023 31 3 729 743 10.1016/j.ymthe.2022.12.011 36560881
    [Google Scholar]
  93. Shi T. Polderman P.E. Pagès-Gallego M. van Es R.M. Vos H.R. Burgering B.M.T. Dansen T.B. p53 forms redox-dependent protein–protein interactions through cysteine 277. Antioxidants 2021 10 10 1578 10.3390/antiox10101578 34679713
    [Google Scholar]
  94. Gencheva R. Arnér E.S.J. Thioredoxin reductase inhibition for cancer therapy. Annu. Rev. Pharmacol. Toxicol. 2022 62 1 177 196 10.1146/annurev‑pharmtox‑052220‑102509 34449246
    [Google Scholar]
  95. Burits M. Bucar F. Antioxidant activity of Nigella sativa essential oil. Phytother. Res. 2000 14 5 323 328 10.1002/1099‑1573(200008)14:5<323::AIDPTR621>3.0.CO;2‑Q 10925395
    [Google Scholar]
  96. Tiji S. Benayad O. Berrabah M. El Mounsi I. Mimouni M. Phytochemical profile and antioxidant activity of Nigella sativa L growing in Morocco. ScientificWorldJournal 2021 2021 1 12 10.1155/2021/6623609 33986636
    [Google Scholar]
  97. Dastjerdi M. Mehdiabady E. Iranpour F. Bahramian H. Effect of thymoquinone on P53 gene expression and consequence apoptosis in breast cancer cell line. Int. J. Prev. Med. 2016 7 1 66 10.4103/2008‑7802.180412 27141285
    [Google Scholar]
  98. Alberts A. Moldoveanu E.T. Niculescu A.G. Grumezescu A.M. Nigella sativa: A comprehensive review of its therapeutic potential, pharmacological properties, and clinical applications. Int. J. Mol. Sci. 2024 25 24 13410 10.3390/ijms252413410 39769174
    [Google Scholar]
  99. Tsukamoto S. Natural products that target p53 for cancer therapy. J. Nat. Med. 2025 79 4 725 737 10.1007/s11418‑025‑01906‑6 40295432
    [Google Scholar]
  100. Ben Abid S. Sahnoun M. Yacoubi-Hadj Amor I. Abdelmoula-Souissi S. Hassairi H. Mokdad-Gargouri R. Gargouri A. New phage display-isolated heptapeptide recognizing the regulatory carboxy-terminal domain of human tumour protein p53. Protein J. 2017 36 5 443 452 10.1007/s10930‑017‑9730‑1 28710679
    [Google Scholar]
  101. Ben Abid S. Ketata E. Yacoubi I. Djemal L. Abdelmoula-Souissi S. Koubaa A. Mokdad-Gargouri R. Gargouri A. Phage libraries screening on P53: Yield improvement by zinc and a new parasites-integrating analysis. PLoS One 2024 19 10 e0297338 10.1371/journal.pone.0297338 39361673
    [Google Scholar]
  102. Di Ventura B. Funaya C. Antony C. Knop M. Serrano L. Reconstitution of Mdm2-dependent post-translational modifications of p53 in yeast. PLoS One 2008 3 1 e1507 10.1371/journal.pone.0001507 18231594
    [Google Scholar]
  103. Abdelmoula-Souissi S. Zouari N. Miladi-Abdenadher I. Yaich-Kolsi O. Ayadi-Masmoudi I. Khabir A. Masmoudi H. Frikha M. Mokdad-Gargouri R. Secreted recombinant P53 protein from Pichia pastoris is a useful antigen for detection of serum p53: Autoantibody in patients with advanced colorectal adenocarcinoma. Mol. Biol. Rep. 2013 40 5 3865 3872 10.1007/s11033‑012‑2467‑1 23526366
    [Google Scholar]
  104. Mokdad-Gargouri R. Abdelmoula-Soussi S. Hadiji-Abbès N. Amor I.Y.H. Borchani-Chabchoub I. Gargouri A. Yeasts as a tool for heterologous gene expression. Methods Mol. Biol. 2012 824 359 370 10.1007/978‑1‑61779‑433‑9_18 22160908
    [Google Scholar]
  105. Wu D. Gallagher D.T. Gowthaman R. Pierce B.G. Mariuzza R.A. Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen. Nat. Commun. 2020 11 1 2908 10.1038/s41467‑020‑16755‑y 32518267
    [Google Scholar]
  106. Tran A.M. Nguyen T.T. Nguyen C.T. Huynh-Thi X.M. Nguyen C.T. Trinh M.T. Tran L.T. Cartwright S.P. Bill R.M. Tran-Van H. Pichia pastoris versus Saccharomyces cerevisiae: A case study on the recombinant production of human granulocyte-macrophage colony-stimulating factor. BMC Res. Notes 2017 10 1 148 10.1186/s13104‑017‑2471‑6 28376863
    [Google Scholar]
  107. Pan Y. Yang J. Wu J. Yang L. Fang H. Current advances of Pichia pastoris as cell factories for production of recombinant proteins. Front. Microbiol. 2022 13 1059777 10.3389/fmicb.2022.1059777 36504810
    [Google Scholar]
  108. Zhu L. Cui X. Hu S. Wang S. Zhang G. Analysis of signal peptides and secreted proteins in the whole proteome of Pichia pastoris. Sheng Wu Gong Cheng Xue Bao 2024 40 3 834 846 10.13345/j.cjb.230512 38545981
    [Google Scholar]
  109. Dong X. Li C. Deng C. Liu J. Li D. Zhou T. Yang X. Liu Y. Guo Q. Feng Y. Yu Y. Wang Z. Guo W. Zhang S. Cui H. Jiang C. Wang X. Song X. Sun X. Cao L. Regulated secretion of mutant p53 negatively affects T lymphocytes in the tumor microenvironment. Oncogene 2024 43 2 92 105 10.1038/s41388‑023‑02886‑1 37952080
    [Google Scholar]
  110. Zavec D. Gasser B. Mattanovich D. Characterization of methanol utilization negative Pichia pastoris for secreted protein production: New cultivation strategies for current and future applications. Biotechnol. Bioeng. 2020 117 5 1394 1405 10.1002/bit.27303 32034758
    [Google Scholar]
  111. Szilagyi A. Digestion, absorption, metabolism, and physiological effects of lactose. Lactose. Cambridge, Massachusetts Academic Press 2019 49 111 10.1016/B978‑0‑12‑811720‑0.00002‑7
    [Google Scholar]
  112. Sellick C.A. Campbell R.N. Reece R.J. Galactose metabolism in yeast-structure and shaped (mottled) cell regulation of the leloir pathway enzymes and the genes encoding them. Int. Rev. Cell Mol. Biol. 2008 269 111 150 10.1016/S1937‑6448(08)01003‑4 18779058
    [Google Scholar]
  113. Harrison M.C. LaBella A.L. Hittinger C.T. Rokas A. The evolution of the GALactose utilization pathway in budding yeasts. Trends Genet. 2022 38 1 97 106 10.1016/j.tig.2021.08.013 34538504
    [Google Scholar]
  114. Maslanka R. Bednarska S. Zadrag-Tecza R. Virtually identical does not mean exactly identical: Discrepancy in energy metabolism between glucose and fructose fermentation influences the reproductive potential of yeast cells. Arch. Biochem. Biophys. 2024 756 110021 10.1016/j.abb.2024.110021 38697344
    [Google Scholar]
  115. Guimier A. Gordon C.T. Godard F. Ravenscroft G. Oufadem M. Vasnier C. Rambaud C. Nitschke P. Bole-Feysot C. Masson C. Dauger S. Longman C. Laing N.G. Kugener B. Bonnet D. Bouvagnet P. Di Filippo S. Probst V. Redon R. Charron P. Rötig A. Lyonnet S. Dautant A. de Pontual L. di Rago J.P. Delahodde A. Amiel J. Biallelic PPA2 mutations cause sudden unexpected cardiac arrest in infancy. Am. J. Hum. Genet. 2016 99 3 666 673 10.1016/j.ajhg.2016.06.021 27523598
    [Google Scholar]
  116. Xiao Z. Zhao Y. Wang Y. Tan X. Wang L. Mao J. Zhang S. Lu Q. Hu F. Zuo S. Liu J. Shan Y. Sucrose-driven carbon redox rebalancing eliminates the Crabtree effect and boosts energy metabolism in yeast. Nat. Commun. 2025 16 1 5211 10.1038/s41467‑025‑60578‑8 40473667
    [Google Scholar]
  117. Qin N. Li L. Ji X. Pereira R. Chen Y. Yin S. Li C. Wan X. Qiu D. Jiang J. Luo H. Zhang Y. Dong G. Zhang Y. Shi S. Jessen H.J. Xia J. Chen Y. Larsson C. Tan T. Liu Z. Nielsen J. Flux regulation through glycolysis and respiration is balanced by inositol pyrophosphates in yeast. Cell 2023 186 4 748 763.e15 10.1016/j.cell.2023.01.014 36758548
    [Google Scholar]
  118. Yako H. Niimi N. Kato A. Takaku S. Tatsumi Y. Nishito Y. Kato K. Sango K. Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions. Sci. Rep. 2021 11 1 18910 10.1038/s41598‑021‑98082‑w 34556698
    [Google Scholar]
  119. Melanson B.D. Bose R. Hamill J.D. Marcellus K.A. Pan E.F. McKay B.C. The role of mRNA decay in p53-induced gene expression. RNA 2011 17 12 2222 2234 10.1261/rna.030122.111 22020975
    [Google Scholar]
  120. Bruer M. Reinhardt D. Welte K. Thakur B.K. Insights into the limitations of transient expression systems for the functional study of p53 acetylation site and oncogenic mutants. Biochem. Biophys. Res. Commun. 2020 524 4 990 995 10.1016/j.bbrc.2020.02.002 32061389
    [Google Scholar]
  121. Aylon Y. Oren M. p53: Guardian of ploidy. Mol. Oncol. 2011 5 4 315 323 10.1016/j.molonc.2011.07.007 21852209
    [Google Scholar]
  122. Crandall J.G. Fisher K.J. Sato T.K. Hittinger C.T. Ploidy evolution in a wild yeast is linked to an interaction between cell type and metabolism. PLoS Biol. 2023 21 11 e3001909 10.1371/journal.pbio.3001909 37943740
    [Google Scholar]
  123. Barker J. Murray A. Bell S.P. Cell integrity limits ploidy in budding yeast. G3 2025 15 2 jkae286 10.1093/g3journal/jkae286 39804723
    [Google Scholar]
  124. Mohammadi S. Saberidokht B. Subramaniam S. Grama A. Scope and limitations of yeast as a model organism for studying human tissue-specific pathways. BMC Syst. Biol. 2015 9 1 96 10.1186/s12918‑015‑0253‑0 26714768
    [Google Scholar]
  125. Laurent J.M. Garge R.K. Teufel A.I. Wilke C.O. Kachroo A.H. Marcotte E.M. Humanization of yeast genes with multiple human orthologs reveals functional divergence between paralogs. PLoS Biol. 2020 18 5 e3000627 10.1371/journal.pbio.3000627 32421706
    [Google Scholar]
  126. Garge R.K. Laurent J.M. Kachroo A.H. Marcotte E.M. Systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes. Genetics 2020 215 4 1153 1169 10.1534/genetics.120.303378 32522745
    [Google Scholar]
  127. Sheng R. Qin Z.H. History and current status of autophagy research. Adv. Exp. Med. Biol. 2019 1206 3 37 10.1007/978‑981‑15‑0602‑4_1 31776978
    [Google Scholar]
  128. Billant O. Blondel M. Voisset C. p53, p63 and p73 in the wonderland of S. cerevisiae. Oncotarget 2017 8 34 57855 57869 10.18632/oncotarget.18506 28915717
    [Google Scholar]
  129. Lion M. Raimondi I. Donati S. Jousson O. Ciribilli Y. Inga A. Evolution of p53 transactivation specificity through the lens of a yeast-based functional assay. PLoS One 2015 10 2 e0116177 10.1371/journal.pone.0116177 25668429
    [Google Scholar]
  130. Resnick M.A. Inga A. Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity. Proc. Natl. Acad. Sci. USA 2003 100 17 9934 9939 10.1073/pnas.1633803100 12909720
    [Google Scholar]
  131. Fischer M. Census and evaluation of p53 target genes. Oncogene 2017 36 28 3943 3956 10.1038/onc.2016.502 28288132
    [Google Scholar]
  132. Fischer M. Schwarz R. Riege K. DeCaprio J.A. Hoffmann S. TargetGeneReg 2.0: A comprehensive web-atlas for p53, p63, and cell cycle-dependent gene regulation. NAR Cancer 2022 4 1 zcac009 10.1093/narcan/zcac009 35350773
    [Google Scholar]
  133. Tebaldi T. Zaccara S. Alessandrini F. Bisio A. Ciribilli Y. Inga A. Whole-genome cartography of p53 response elements ranked on transactivation potential. BMC Genomics 2015 16 1 464 10.1186/s12864‑015‑1643‑9 26081755
    [Google Scholar]
  134. Nguyen T.A.T. Grimm S.A. Bushel P.R. Li J. Li Y. Bennett B.D. Lavender C.A. Ward J.M. Fargo D.C. Anderson C.W. Li L. Resnick M.A. Menendez D. Revealing a human p53 universe. Nucleic Acids Res. 2018 46 16 8153 8167 10.1093/nar/gky720 30107566
    [Google Scholar]
  135. Pant V. Sun C. Lozano G. Tissue specificity and spatio-temporal dynamics of the p53 transcriptional program. Cell Death Differ. 2023 30 4 897 905 10.1038/s41418‑023‑01123‑2 36755072
    [Google Scholar]
  136. Farooqi K. Ghazvini M. Pride L.D. Mazzella L. White D. Pramanik A. Bargonetti J. Moore C.W. A protein in the yeast Saccharomyces cerevisiae presents DNA binding homology to the p53 checkpoint protein and tumor suppressor. Biomolecules 2020 10 3 417 10.3390/biom10030417 32156076
    [Google Scholar]
  137. Kocaefe-Özşen N. Yilmaz B. Alkım C. Arslan M. Topaloğlu A. Kısakesen H. Gülsev E. Çakar Z.P. Physiological and molecular characterization of an oxidative stress-resistant Saccharomyces cerevisiae strain obtained by evolutionary engineering. Front. Microbiol. 2022 13 822864 10.3389/fmicb.2022.822864 35283819
    [Google Scholar]
/content/journals/mrmc/10.2174/0113895575419074251111110239
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Human P53 Expression in Yeast: Investigating Its Apoptotic Effects
Bentham Science Publishers ; https://doi.org/10.2174/0113895575419074251111110239
/content/journals/mrmc/10.2174/0113895575419074251111110239
/content/journals/mrmc/10.2174/0113895575419074251111110239
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  • Article Type:     Review Article
Keywords: p53 mutation ; apoptosis ; yeast ; mitochondria ; thioredoxin ; p53 ; oxidative stress ; cell death

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