Cell and Tissue BiologyCell and Tissue BiologyЦитология0041-37713034-6061The Russian Academy of Sciences67746510.31857/S0041377124050028DUXBQUArticlesСтатьиResearch ArticlePost-translational regulation of the p53 tumor suppressor activityПосттрансляционная регуляция активности онкосупрессора р53RomanovaA. A.РомановаА. А.
Russian Federation
angeliina.romanova@outlook.comGrigoryevaT. A.ГригорьеваТ. А.
Russian Federation
angeliina.romanova@outlook.comTribulovichV. G.ТрибуловичВ. Г.
Russian Federation
angeliina.romanova@outlook.comSaint Petersburg State Institute of TechnologyСанкт-Петербургский государственный технологический институт (технический университет)15112024665-640741920032025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://vietnamjournal.ru/0041-3771/article/view/677465

P53, encoded by the TP53 gene, has attracted researchers’ interest for several decades as a key human tumor suppressor protein. P53-mediated tumor suppression is achieved through transactivation of its target genes, or as a consequence of direct binding of p53 to protein targets that are involved in the regulation of various cellular processes. The review briefly discusses mechanisms involved in the regulation of p53 activity at the protein level – from oligomerization required for the implementation of p53 transactivation mechanisms to ubiquitin-dependent proteolysis that maintains a low level of this proapoptotic protein in normal cells. The main enzymes involved in various post-translational modifications and the effects they can lead to are noted. Rational intervention in these pathways at one stage or another can be relevant both for research purposes and in the applied aspect, particularly for the anti-cancer drug development.

Транскрипционный фактор р53, кодируемый геном TP53, на протяжении нескольких десятилетий приковывает к себе интерес исследователей как ключевой онкосупрессорный белок человека. Опосредованное р53 подавление развития опухоли осуществляется за счет трансактивации его генов-мишеней, либо в результате прямого связывания р53 с белковыми мишенями, которые участвуют в регуляции различных клеточных процессов. В обзоре кратко обсуждаются механизмы, задействованные в регуляции активности р53 на белковом уровне – от олигомеризации, необходимой для реализации трансактивационных механизмов р53, до убиквитин-зависимого протеолиза, поддерживающего низкий уровень этого проапоптотического белка в нормальных клетках. Отмечены основные ферменты, участвующие в различных посттрансляционных модификациях, и эффекты, к которым они могут приводить. Рациональное вмешательство в эти пути на том или ином этапе может быть актуально как в исследовательских целях, так и в прикладном аспекте, в частности, для разработки противоопухолевых препаратов.

p53post-translational modifications (PTM)E3-ubiquitin ligasesp53посттрансляционные модификации (ПТМ)E3-убиквитинлигазыРоссийский научный фондRussian Science Foundation23-13-00344Асатурова А.В. 2015. Изоформы белка р53: роль в норме и патологии, особенности выявления и клиническое значение. Успехи современного естествознания. № 3. С. 9. (Asaturova A.V. 2015. Isoforms of p53 protein: role in norm and pathology, features of detection and clinical significance. Successes of Modern Natural Science. No. 3. P. 3.)Дакс А.А., Мелино Д., Барлев Н.А. 2013. Роль различных Е3-убиквитинлигаз в регуляции активности онкосупрессора р53. Цитология. Т. 55. № 10. C. 673. (Daks A.A., Melino D., Barlev N.A. 2013. The role of different E3 ubiquitin ligases in regulation of the p53 tumor suppressor protein. Tsitologiya. V. 55. P. 673.)Желтухин А.О., Чумаков П.М. 2010. Повседневные и индуцируемые функции гена р53. Успехи биол. химии. Т. 50. № 1. C. 447. (Zheltuhin A.O., Chumakov P.M. 2010. Constitutive and induced functions of the p53 gene. Biochemistry (Moscow). V. 75. P. 1692. https://doi.org/10.1134/s0006297910130110)Чумаков, П.М. 2007. Белок р53 и его универсальные функции в многоклеточном организме. Успехи биологической химии. Т. 47. № 1. С. 3. (Chumakov P.M. 2007. Р53 protein and its universal functions in the multicellular organism. Adv. Biol. Chem. V. 47. P. 3.)Шувалов О.Ю., Федорова О.А., Петухов А.В., Дакс А.А., Васильева Е.А., Григорьева Т,А., Иванов Г.С., Барлев Н.А. 2015. Негативные регуляторы онкосупрессора р53 в контексте направленной противоопухолевой терапии. Цитология. Т. 57. № 12. C. 847. (Shuvalov O. Yu., Fedorova O.A., Petukhov A.V., Daks A.A., Vasilieva E.A., Grigorieva T.A., Ivanov G.S., Barlev N.A. 2015. Negative regulators of tumor suppressor p53 in the context of anticancer therapy. Tsitologiya. V. 57. P. 847.)Amendolare A., Marzano F., Petruzzella V., Vacca R.A., Guerrini L., Pesole G., Sbisa E., Tullo A.T. 2022. The underestimated role of the p53 pathway in renal cancer. Cancers. V. 14. Art. ID 5733. https://doi.org/10.3390/cancers14235733Antoniou N., Lagopati N., Balourdas D.I., Nikolaou M., Papalampros A., Vasileiou P.V.S., Myrianthopoulos V., Kotsinas A., Shiloh Y., Liontos M., Gorgoulis V.G. 2019. The role of E3, E4 ubiquitin ligase (UBE4B) in human pathologies. Cancers. V. 12. P. 62. https://doi.org/10.3390/cancers12010062Auclair Y., Richard S. 2013. The role of arginine methylation in the DNA damage response. DNA Repair (Amst). V. 12. P. 459. https://doi.org/10.1016/j.dnarep.2013.04.006.Bai L., Zhu W.G. 2006. P53: structure, function and therapeutic applications. J. Cancer Mol. V. 2. P. 141.Baranes-Bachar K., Levy-Barda A., Oehler J., Reid D.A., Soria-Bretones I., Voss T.C., Chung D., Park Y., Liu C., Yoon J.B., Li W., Dellaire G., Misteli T., Huertas P., Rothenberg E. et al. 2018. The ubiquitin E3/E4 ligase UBE4A adjusts protein ubiquitylation and accumulation at sites of DNA damage, facilitating double-strand break repair. Mol. Cell. V. 69. P. 866. https://doi.org/10.1016/j.molcel.2018.02.002Bettermann K., Benesch M., Weis S., Haybaeck J. 2012. SUMOylation in carcinogenesis. Cancer Lett. V. 316. P. 113. https://doi.org/10.1016/j.canlet.2011.10.036Brooks C.L., Gu W. 2006. P53 ubiquitination: Mdm2 and beyond. Mol. Cell. V. 21. P. 307. https://doi.org/10.1016/j.molcel.2006.01.020Bulatov E., Sayarova R., Mingaleeva R., Miftakhova R., Gomzikova M., Ignatyev Y., Petukhov A., Davidovich P., Rizvanov A., Barlev N.A. 2018. Isatin-Schiff base-copper (II) complex induces cell death in p53-positive tumors. Cell Death Discov. V. 4. P. 103. https://doi.org/10.1038/s41420-018-0120-zCapuozzo M., Santorsola M., Bocchetti M., Perri F., Cascella M., Granata V., Celotto V., Gualillo O., Cossu A.M., Nasti G., Caraglia M., Ottaiano A. 2022. P53: from fundamental biology to clinical applications in cancer. Biology (Basel). V. 11. Art. ID 1325. https://doi.org/10.3390/biology11091325Chen D., Brooks C.L., Gu W. 2006. ARF-BP1 as a potential therapeutic target. Br. J. Cancer. V. 94. P. 1555. https://doi.org/10.1038/sj.bjc.6603119Chillemi G., Davidovich P., D’Abramo M., Mametnabiev T., Garabadzhiu A.V., Desideri A., Melino G. 2013. Molecular dynamics of the full-length p53 monomer. Cell Cycle. V. 12. P. 3098. https://doi.org/10.4161/cc.26162Duffy M.J., Synnott N.C., O’Grady S., Crown J. 2022. Targeting p53 for the treatment of cancer. Semin. Cancer Biol. V. 79. P. 58. https://doi.org/10.1016/j.semcancer.2020.07.005Fedorova O., Daks A., Petrova V., Petukhov A., Lezina L., Shuvalov O., Davidovich P., Kriger D., Lomert E., Tentler D., Kartsev V., Uyanik B., Tribulovich V., Demidov O., Melino G. et al. 2018. Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis. Cell Cycle. V. 17. P. 1917. https://doi.org/10.1080/15384101.2018.1506664Fedorova O., Petukhov A., Daks A., Shuvalov O., Leonova T., Vasileva E., Aksenov N., Melino G., Barlev N.A. 2019. Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis. Oncogene. V. 38. P. 2108. https://doi.org/10.1038/s41388-018-0566-8Fischer N.W., Prodeus A., Malkin D., Gariépy J. 2016. P53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis. Cell Cycle. V. 15. P. 3210. https://doi.org/10.1080/15384101.2016.1241917Gaglia G., Guan Y., Shah J.V., Lahav G. 2013. Activation and control of p53 tetramerization in individual living cells. Proc. Natl. Acad. Sci. USA. V. 110. P. 15497. https://doi.org/10.1073/pnas.1311126110Gencel-Augusto J., Lozano G. 2020. P53 tetramerization: at the center of the dominant-negative effect of mutant p53. Genes Dev. V. 34. P. 1128. https://doi.org/10.1101/gad.340976.120Grigoreva T.A., Novikova D.S., Melino G., Barlev N.A., Tribulovich V.G. 2024. Ubiquitin recruiting chimera: more than just a PROTAC. Biology Direct. V. 19. P. 55. https://doi.org/10.1186/s13062-024-00497-8Grigoreva T.A., Novikova D.S., Petukhov A.V., Gureev M.A, Garabadzhiu A.V., Melino G., Barlev N.A., Tribulovich V.G. 2017. Proapoptotic modification of substituted isoindolinones as MDM2-p53 inhibitors. Bioorg. Med. Chem. Lett. V. 27. P. 5197. https://doi.org/10.1016/j.bmcl.2017.10.049Grigoreva T., Romanova A., Sagaidak A., Vorona S., Novikova D., Tribulovich V. 2020. Mdm2 inhibitors as a platform for the design of P-glycoprotein inhibitors. Bioorg. Med. Chem. Lett. V. 30. Art. ID 127424. https://doi.org/10.1016/j.bmcl.2020.127424Guo T., Gu C. 2017. New insights into regulation of p53 protein degradation. Int. J. Clin. Exp. Med. V. 10. Art. ID 8773Gureev M., Novikova D., Grigoreva T., Vorona S., Garabadzhiu A., Tribulovich V. 2020. Simulation of MDM2 N-terminal domain conformational lability in the presence of imidazoline based inhibitors of MDM2-p53 protein-protein interaction. J. Comput. Aided. Mol. Des. V. 34. P. 55. https://doi.org/10.1007/s10822-019-00260-6Han D., Huang M., Wang T., Li Z., Chen Y., Liu C., Lei Z., Chu X. 2019. Lysine methylation of transcription factors in cancer. Cell Death Dis. V. 10. P. 290. https://doi.org/10.1038/s41419-019-1524-2Horikawa I., Park K.Y., Isogaya K., Hiyoshi Y., Li H., Anami K., Robles A.I., Mondal A.M., Fujita K., Serrano M., Harris C.C. 2017. Δ133p53 represses p53-inducible senescence genes and enhances the generation of human induced pluripotent stem cells. Cell Death Diff. V. 24. P. 1017. https://doi.org/10.1038/cdd.2017.48Horvat A., Tadijan A., Vlašić I., Slade N. 2021. P53/p73 protein network in colorectal cancer and other human malignancies. Cancers. V. 13.Art. ID 2885. https://doi.org/10.3390/cancers13122885Hernandez Borrero L.J., El-Deiry W.S. 2021. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim. Biophys. Acta. Rev. Cancer. V. 1876. Art. ID 188556. https://doi.org/10.1016/j.bbcan.2021.188556Ivanov G.S., Ivanova T., Kurash J., Ivanov A., Chuikov S., Gizatullin F., Herrera-Medina E.M., Rauscher F. 3rd, Reinberg D., Barlev N.A. 2007. Methylation-acetylation interplay activates p53 in response to DNA damage. Mol. Cell Biology. V. 27. P. 6756. https://doi.org/10.1128/MCB.00460-07Jansson M., Durant S.T., Cho E.C., Sheahan S., Edelmann M., Kessler B., La Thangue N.B. 2008. Arginine methylation regulates the p53 response. Nat. Cell Biol. V. 10. P. 1431. https://doi.org/10.1038/ncb1802Joerger A.C., Fersht A.R. 2010. The tumor suppressor p53: from structures to drug discovery. Cold Spring Harb. Perspect. Biol. V. 2. Art. ID a000919. https://doi.org/10.1101/cshperspect.a000919Ka W.H., Cho S.K., Chun B.N., Byun S.Y., Ahn J.C. 2018. The ubiquitin ligase COP1 regulates cell cycle and apoptosis by affecting p53 function in human breast cancer cell lines. Breast Cancer. V. 25. P. 529. https://doi.org/10.1007/s12282-018-0849-5Kamada R., Toguchi Y., Nomura T., Imagawa T., Sakaguchi K. 2016. Tetramer formation of tumor suppressor protein p53: Structure, function, and applications. Peptide Science. V. 106. P. 598. https://doi.org/10.1002/bip.22772Kim S., An S. 2016. Role of p53 isoforms and aggregations in cancer. Medicine (Baltimore). V. 95. Art. ID e3993. https://doi.org/10.1097/MD.0000000000003993Klein A.M., de Queiroz R.M., Venkatesh D., Prives C. 2021. The roles and regulation of MDM2 and MDMX: it is not just about p53. Genes Dev. V. 35. P. 575. https://doi.org/10.1101/gad.347872.120Krasavin M., Gureyev M., Dar’in D., Bakulina O., Chizhova M., Lepikhina A.,Novikova D., Grigoreva T., Ivanov G., Zhumagalieva A., Garabadzhiu A.V., Tribulovich V. 2018. Design; in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction. Bioorg. Med. Chem. V. 26. P. 2651. https://doi.org/10.1016/j.bmc.2018.04.036Kuang L., Jiang Y., Li C., Jiang Y. 2021. WW domain-containing E3 ubiquitin protein ligase 1: a self-disciplined oncoprotein. Front. Cell Dev. Biol. V. 9. Art. ID 757493. https://doi.org/10.3389/fcell.2021.757493Laine A., Topisirovic I., Zhai D., Reed J.C., Borden K.L., Ronai Z. 2006. Regulation of p53 localization and activity by Ubc13. Mol. Cell Biol. V. 26. P. 8901. https://doi.org/10.1128/MCB.01156-06Lang V., Pallara C., Zabala A., Lobato-Gil S., Lopitz-Otsoa F., Farrás R., Hjerpe R., Torres-Ramos M., Zabaleta L., Blattner C., Hay R.T., Barrio R., Carracedo A., Fernandez-Recio J., Rodríguez M.S. et al. 2014. Tetramerization-defects of p53 result in aberrant ubiquitylation and transcriptional activity. Mol. Oncol. V. 8. P. 1026. https://doi.org/10.1016/j.molonc.2014.04.002Lee S.W., Seong M.W., Jeon Y. J., Chung C.H. 2012. Ubiquitin E3 ligases controlling p53 stability. Animal Cells Syst. V. 16. P. 173. https://doi.org/101080/19768354.2012.688769Leng R.P., Lin Y., Ma W., Wu H., Lemmers B., Chung S., Parant J.M., Lozano G., Hakem R., Benchimol S. 2003. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell. V. 112. P. 779. https://doi.org/10.1016/s0092-8674(03)00193-4Lezina L, Aksenova V, Fedorova O, Malikova D, Shuvalov O, Antonov A.V., Tentler D., Garabadgiu A.V., Melino G., Barlev N.A. 2015. KMT Set7/9 affects genotoxic stress response via the Mdm2 axis. Oncotarget. V. 6. Art. ID 25843. https://doi.org/10.18632/oncotarget.4584Li X., Pu W., Zheng Q., Ai M., Chen S., Peng Y. 2022. Proteolysis-targeting chimeras (PROTACs) in cancer therapy. Mol. Cancer. V. 21. P. 99. https://doi.org/10.1186/s12943-021-01434-3Liebl M.C., Hofmann T.G. 2021. The role of p53 signaling in colorectal cancer. Cancers (Basel). V. 13. Art. ID 2125. https://doi.org/10.3390/cancers13092125Liu J., Zhang C., Wang X., Hu W., Feng Z. 2021. Tumor suppressor p53 cross-talks with TRIM family proteins. Genes Dis. V. 8. P. 463. https://doi.org/10.1016/j.gendis.2020.07.003Liu Y., Tavana O., Gu W. 2019. P53 modifications: exquisite decorations of the powerful guardian. J. Mol. Cell Biol. V. 11. P. 564. https://doi.org/10.1093/jmcb/mjz060Lubin D.J., Butler J.S., Loh S.N. 2010. Folding of tetrameric p53: oligomerization and tumorigenic mutations induce misfolding and loss of function. J. Mol. Biol. V. 395. P. 705. https://doi.org/10.1016/j.jmb.2009.11.013Marine J.C. 2012. Spotlight on the role of COP1 in tumorigenesis. Nat. Rev. Cancer. V. 7. P. 455. https://doi.org/10.1038/nrc3271Mehta S., Campbell H., Drummond C.J., Li K., Murray K., Slatter T., Bourdon J.C., Braithwaite A.W. 2021. Adaptive homeostasis and the p53 isoform network. EMBO Reports. V. 22. Art. ID e53085. https://doi.org/10.15252/embr.202153085Mittenberg A.G., Moiseeva T.N., Barlev N.A. 2018 Role of proteasomes in transcription and their regulation by covalent modifications. Front. Biosci. V. 13. P. 7184. https://doi.org/10.2741/3220Moll U.M., Wolff S., Speidel D., Deppert W. 2005. Transcription-independent pro-apoptotic functions of p53. Curr. Opin. Cell Biol. V. 17. P. 631. https://doi.org/10.1016/j.ceb.2005.09.007Nagpal I., Yuan Z. 2021. The basally expressed p53-mediated homeostatic function. Front. Cell Dev. Biol. V. 9. Art. ID 775312. https://doi.org/10.3389/fcell.2021.775312Osterburg C., Dötsch V. 2022. Structural diversity of p63 and p73 isoforms. Cell Death Differ. V. 29. P. 921. https://doi.org/10.1038/s41418-022-00975-4Pan M., Blattner C. 2021. Regulation of p53 by E3s. Cancers. V. 13. Art. ID 745. https://doi.org/10.3390/cancers13040745.Rada M., Vasileva E., Lezina L., Marouco D., Antonov A.V., Macip S., Melino G., Barlev N.A. 2016. Human EHMT2/G9a activates p53 through methylation-independent mechanism. Oncogene. V. 36. P. 922. https://doi.org/10.1038/onc.2016.258Reed S.M., Quelle D.E. 2014. P53 acetylation: regulation and consequences. Cancers. V. 7. Art. ID 30. https://doi.org/10.3390/cancers7010030Rodriguez M.S., Desterro J.M., Lain S., Lane D.P., Hay R.T. 2000. Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol. Cell Biol. V. 20. P. 8458. https://doi.org/10.1128/MCB.20.22.8458-8467.2000Scoumanne A., Chen X. 2008. Protein methylation: a new regulator of the p53 tumor suppressor. Histol. Histopathol. V. 23. Art. ID 1143. https://doi.org/10.14670/hh-23.1143Sharif J., Tsuboi A., Koseki H. 2010. TOPORS (topoisomerase I binding, arginine/serine-rich). Atlas Genet. Cytogenet. Oncol. Haematol. V. 14. P. 263.Sheng Y., Laister R.C., Lemak A., Wu B., Tai E., Duan S., Lukin J, Sunnerhagen M., Srisailam S., Karra M., Benchimol S., Arrowsmith C.H. 2008. Molecular basis of Pirh2-mediated p53 ubiquitylation. Nat. Struct. Mol. Biol. V. 15. P. 1334. https://doi.org/10.1038/nsmb.1521Sheren J.E., Kassenbrock C.K. 2013. RNF38 encodes a nuclear ubiquitin protein ligase that modifies p53. Biochem. Biophys. Res. Commun. V. 440. P. 473. https://doi.org/10.1016/j.bbrc.2013.08.031Steffens Reinhardt L., Zhang X., Groen K., Morten B.C., De Iuliis G.N., Braithwaite A.W., Bourdon J.C., Avery-Kiejda K.A. 2022. Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage. Cell Death Dis. V. 13. P. 907. https://doi.org/10.1038/s41419-022-05349-9Sykes S.M., Mellert H.S., Holbert M.A., Li K., Marmorstein R., Lane W.S., McMahon S.B. 2006. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol. Cell. V. 24. P. 841. https://doi.org/10.1016/j.molcel.2006.11.026Synoradzki K.J., Bartnik E., Czarnecka A.M., Fiedorowicz M., Firlej W., Brodziak A., Stasinska A., Rutkowski P., Grieb P. 2021. TP53 in biology and treatment of osteosarcoma. Cancers (Basel). V. 13. P. 4284. https://doi.org/10.3390/cancers13174284Tang Y., Zhao W., Chen Y., Zhao Y., Gu W. 2008. Acetylation is indispensable for p53 activation. Cell. V. 133. P. 612. https://doi.org/10.1016/j.cell.2008.03.025Vieler M., Sanyal S. 2018. P53 isoforms and their implications in cancer. Cancers (Basel). V. 10. Art. ID 288. https://doi.org/10.3390/cancers10090288Vlasic I., Horvat A., Tadijan A., Slade N. 2022. P53 family in resistance to targeted therapy of melanoma. Int. J. Mol. Sci. V. 24. Art. ID 65. https://doi.org/10.3390/ijms24010065Wang F., He L., Huangyang P., Liang J., Si W., Yan R., Han X., Liu S., Gui B., Li W., Miao D., Jing C., Liu Z., Pei F., Sun L. et al. 2014. JMJD6 promotes colon carcinogenesis through negative regulation of p53 by hydroxylation. PLoS Biol. V. 12. Art. ID e1001819. https://doi.org/10.1371/journal.pbio.1001819Wang H., Guo M., Wei H., Chen Y. 2023. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Signal Transduct. Target. Ther. V. 8. P. 92. https://doi.org/10.1038/s41392-023-01347-1Wang Y., Zhang Ch., Wang J., Liu J. 2022. P53 regulation by ubiquitin and ubiquitin-like modifications. Gen. Instab. Dis. V. 3. P. 179. https://doi.org/101007/s42764-022-00067-0Wen J., Wang D. 2021. Deciphering the PTM codes of the tumor suppressor p53. J. Mol. Cell Biol. V. 13. P. 774.Wesche J., Kühn S., Kessler B.M., Salton M., Wolf A. 2017. Protein arginine methylation: a prominent modification and its demethylation. Cell. Mol. Life Sci. V. 74. P. 3305. https://doi.org/10.1007/s00018-017-2515-zWest L.E., Gozani O. 2011. Regulation of p53 function by lysine methylation. Epigenomics. V. 3. P. 361. https://doi.org/10.2217/EPI.11.21Xu Z., Wu W., Yan H., Hu Y., He Q., Luo P. 2021. Regulation of p53 stability as a therapeutic strategy for cancer. Biochem. Pharmacol. V. 185. Art. ID 114407. https://doi.org/10.1016/j.bcp.2021.114407Yakovlev V.A., Bayden A.S., Graves P.R., Kellogg G.E., Mikkelsen R.B. 2010. Nitration of the tumor suppressor protein p53 at tyrosine 327 promotes p53 oligomerization and activation. Biochemistry. V. 49. P. 5331. https://doi.org/10.1016/j.bcp.2021.114407Yang J., Chen S., Yang Y., Ma X., Shao B., Yang S., Wei Y., Wei X. 2020. Jumonji domain‐containing protein 6 protein and its role in cancer. Cell Prol. V. 53. Art. ID e12747. https://doi.org/10.1111/cpr.12747Zhao L., Sanyal S. 2022. P53 isoforms as cancer biomarkers and therapeutic targets. Cancers (Basel). V. 14. Art. ID 3145. https://doi.org/10.3390/cancers14133145Zhu H., Gao H., Ji Y., Zhou Q., Du Z., Tian L., Jiang Y., Yao K., Zhou Z. 2022. Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials. Oncol. V. 15. P. 91. https://doi.org/10.1186/s13045-022-01314-3