J Mol Biol. Thus, these studies suggest that restoring mutp53 to wild-type conformation is a promising anti-cancer strategy. Targeting a neoantigen derived from a common TP53 mutation. Shin D, Kim EH, Lee J, Roh JL. 2020;80:45269.e459. Zheng X, Liu B, Liu X, Li P, Zhang P, Ye F, et al. 1a), which encode the DNA binding domain, with the most common mutation sites occurring at R175, G245, R248, R249, R273 and R282 (Fig. Thirdly, the current study mainly focuses on mutational hotspots of TP53. Cancer 2001;91:8089. 1991;253:4953. Petitjean A, Achatz MIW, Borresen-Dale AL, Hainaut P, Olivier M. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. However, mutations in TP53 affect T cell recruitment and activity, leading to immune evasion and promoting cancer progression [153]. Similar to wtp53, post-transcriptional modifications such as phosphorylation, acetylation and ubiquitination can also regulate the level of mutp53. Chemosensitivity linked to p73 function. After damage to their DNA, normal cells increase production of p53 protein which acts as a transcription. Google Scholar. Google Scholar. Olivier M, Langerd A, Carrieri P, Bergh J, Klaar S, Eyfjord J, et al. The process of carcinogenesis involves the gain of oncogene activity and the loss of tumor suppressor gene function. Figure adapted from RCSB PDB (PDB 2AC0). BID regulation by p53 contributes to chemosensitivity. Elife. 2020;9:e55994. 2018;34:298314.e297. 2003;11:57790. Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway. 2009;9:691700. Proto-oncogenes stimulate the cell to grow, divide and move through each cell cycle checkpoint to be inspected. Thus, these findings suggest that mutp53 plays a crucial role in regulating chemoresistance of tumor cells. Non-cell-autonomous tumor suppression by p53. The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Int J Cancer. Mol Cell. Additionally, in hepatic stellate cells, wtp53 is translocated to mitochondria through binding to BRD7 and interacts with SLC25A28, which leads to abnormal accumulation of redox-active iron and promotes ferroptosis. Mutp53 is usually located in the nucleus, but in some cases it is located in the cytoplasm, which may be related to the types of mutation [16]. In colorectal cancer, wtp53 inhibits ferroptosis by blocking DPP4 activity in a transcription-independent manner [88]. In esophageal cancer, A:T base pair mutations are more common [39]. In response to DNA damage, mutp53 binds to NF-Y target promoters and recruits p300 to acetylate histones, resulting in overexpression of cell cycle genes and promoting malignant tumor development [56]. Should mutant TP53 be targeted for cancer therapy? 1997;57:4285300. To begin with, mutp53 binds to transcription factors (TFs) in order to perform its function (Fig. Sonego M, Schiappacassi M, Lovisa S, DallAcqua A, Bagnoli M, Lovat F, et al. introduced p53 V143A, R175H, R248W, R273H, and D281G mutants into p53-deficient fibroblasts, resulting in enhanced tumorigenic potential in nude mice [7]. PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development. Mol Cell. Tarangelo A, Magtanong L, Bieging-Rolett KT, Li Y, Ye J, Attardi LD, et al. Science. The gene called P53 is a major player in cancer. Front Endocrinol (Lausanne). 2011;108:1625964. Mol Biol Rep. 2019;46:647184. Tada M, Matsumoto R, Iggo RD, Onimaru R, Shirato H, Sawamura Y, et al. Science. Yu X, Kogan S, Chen Y, Tsang AT, Withers T, Lin H, et al. Cancer Sci. Selective sensitivity to radiation of cerebral glioblastomas harboring p53 mutations. The p53 proto-oncogene can act as a suppressor of transformation. Jethwa A, Sabicki M, Hllein J, Jentzsch M, Dalal V, Rabe S, et al. This is a preview of subscription content, access via your institution. Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. Wtp53 plays an important role in maintaining genome stability as the guardian of genome, whereas mutp53 can promote genome instability (Table 1). This work was supported by grants from the National Key R&D project of the Chinese Ministry of Science and Technology [2018YFE0205100]; the Key Program of the National Natural Science Foundation of China [11875299]; the National Natural Science Foundation of China [11675234]. Nat Rev Cancer. Nature. In fibrosarcoma, wtp53 can regulate the expression of CDKN1A to delay the onset of ferroptosis in response to cystine deprivation [89]. Article To formally exclude this oncogene as the searched-for tumor suppressor, the . In contrast, it is not significantly observed in tumor cells carrying mutp53 (Fig. PI3K/mTOR pathway inhibition overcomes radioresistance via suppression of the HIF1-alpha/VEGF pathway in endometrial cancer. 2019;116:83906. Chen J. Sampath J, Sun D, Kidd VJ, Grenet J, Gandhi A, Shapiro LH, et al. p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. From a large amount of experimental data, it is becoming increasingly clear that mutp53 plays a key role in promoting the malignant phenotype of cancer. Cell Rep. 2020;30:48196.e486. Finlay CA, Hinds PW, Levine AJ. Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Last but not least, mutp53 is generally considered undruggable. Liu DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, et al. Secondly, post-translational modifications play an important role in the accumulation of mutp53. Oncogene Cell. Park EK, Lee JC, Park JW, Bang SY, Yi SA, Kim BK, et al. Although most studies have supported the function of p53 in promoting ferroptosis. Mol Cell Biol. Zhan et al. RETRA, a small molecule compound, can release p73 from mutp53-p73 complex, which inhibits tumor development [164]. 2017;7:a026054. Moreover, mutp53 can be modified by acetylation. 1991;65:108391. Wtp53 suppresses tumorigenesis by promoting an anti-tumor microenvironment and modulates M1 polarization pattern in neighboring macrophages [91]. J Biol Chem. Cancer Cell. APR-246 is also known as PRIMA-1MET, and its active form in vivo is methylene quinuclidinone. A key tumor suppressor gene often lost is p53, which can induce temporary growth arrest and DNA repair, irreversible growth arrest,terminal differentiation, or apoptosis in response to potentially oncogenic cellular stress such as DNA damage . In breast cancer, mutp53 affects TNF-induced activation of NF-B, which exacerbates the inflammatory response [95]. Nat Med. Interestingly, in colon cancer, mutp53 selectively releases miR-1246-rich exosomes that are taken up by surrounding macrophages, leading to miR-1246-dependent reprogramming into a tumor-promoting M2 state [92]. 1985;314:6336. Wang JY, Liu DD, Sun ZW, Ye T, Li JY, Zeng B, et al. Xu Y. Zhang S, Zhou L, Hong B, van den Heuvel AP, Prabhu VV, Warfel NA, et al. Tarangelo A, Magtanong L, Bieging-Rolett KT, Li Y, Ye J, Attardi LD, et al. In lung cancer, mutp53 inhibits the formation of the STING-TBK1-IRF3 complex, leading to inactivation of the innate immune signaling pathway [156]. 2002;21:78318. You are using a browser version with limited support for CSS. 2020;586:1338. b Different mutation types caused by different mechanisms and its impact on tumor development. 2010;29:94956. PubMed p53 moves to mitochondria: a turn on the path to apoptosis. Qiang Li, Hong Zhang or Cuixia Di. 2003;11:57790. 2002;109:33546. There is an extremely high probability of TP53 mutations occurring in clinical tumors. However, most mutations occur in wtp53 DNA binding domain and lead to functional inactivation. Nature. 2016;108:djv303. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. 2018;9:582. https://doi.org/10.3390/genes9120582. Wolff S, Erster S, Palacios G, Moll UM. Genes Dev. Blagih J, Zani F, Chakravarty P, Hennequart M, Pilley S, Hobor S, et al. Dumay A, Feugeas JP, Wittmer E, Lehmann-Che J, Bertheau P, Espie M, et al. Oncogenes, Tumor Suppressor Genes, and DNA Repair Genes. AZD1775 is a potent and selective WEE1 inhibitor that has entered phase II clinical trials (Table 2) (Fig. Evaluation of the CRISPR/Cas9 directed mutant TP53 gene repairing effect in human prostate cancer cell line PC-3. Nat Cell Biol. Notably, cell-in-cell structures have been identified in many solid tumors, wtp53 promotes death of cells that form these structures, whereas mutp53 contributes to formation of cell-in-cell structures in lung adenocarcinoma through live cell engulfment, leading to abnormal mitosis [72]. Nat Struct Mol Biol. Pfeifer GP, Besaratinia A. Mutational spectra of human cancer. Functions of p53 in metabolism and invasion. 2017;170:106278. Some small molecule compounds or peptide drugs can target tumors carrying mutp53 for treatment. Williams AB, Schumacher B. p53 in the DNA-damage-repair process. Furthermore, TP53 mutational spectrum differs among tumors [19, 20]. constructed an SP-C/p53 R273H transgenic mouse model for studying the role of mutp53 in lung tumorigenesis. Nature. 2004;119:86172. Leijen S, van Geel RM, Sonke GS, de Jong D, Rosenberg EH, Marchetti S, et al. Restoring the p53 Guardian Phenotype in p53-Deficient Tumor Cells with CRISPR/Cas9. 2016;18:897909. Induction of apoptosis is one of the most important functions of p53, and disruption of this function can promote tumor chemoresistance [104]. Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: the critical roles of p53. Firstly, TP53 is mutated in more than 50% of tumors, so what are the factors that influence the mutation types and mutation spectrum of TP53? J Biol Chem. Furthermore, we discuss the gain-of-function of mutp53 in cancers: genetic instability, ferroptosis, microenvironment, and stemness. The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis. Dumble M, Xu L, Dominique R, Liu B, Yang H, McBrayer M-K, et al. Herein, in this review, we summarize our understanding of mutp53 types and mutp53 spectrum in cancers. Gynecologic Oncol. Furthermore, treatment of p53 R172H/R172H and p53 R248Q/- mice with ganetespib inhibits tumor growth and prolongs survival in a mutp53-dependent manner, but it has no effect on p53-null mice [149]. TP53 Mutation Spectrum in Breast Cancer Is Subtype Specific and Has Distinct Prognostic Relevance. 2019;116:2425967. Of note, APR-246, COT1-2, PC14586, and Arsenic Trioxide (ATO) are currently undergoing clinical trials (Table 2) (Fig. Di Minin G, Bellazzo A, Dal Ferro M, Chiaruttini G, Nuzzo S, Bicciato S, et al. Cell Death Dis. PubMed Hum Gene Ther. Other E3 ubiquitin ligases such as CHIP, COP1 and Pirh2 can ubiquitinate and degrade mutp53 [51, 52]. Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China, Xiaohua Chen,Taotao Zhang,Wei Su,Zhihui Dou,Dapeng Zhao,Xiaodong Jin,Huiwen Lei,Qiang Li,Hong Zhang&Cuixia Di, Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China, Xiaohua Chen,Qiang Li,Hong Zhang&Cuixia Di, Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China, Xiaohua Chen,Taotao Zhang,Wei Su,Zhihui Dou,Dapeng Zhao,Huiwen Lei,Qiang Li,Hong Zhang&Cuixia Di, School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing, 101408, China, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China, Lanhai Neclear Medical Research Center, Putian, 351100, China, You can also search for this author in However, wtp53 effectively abrogates ionizing radiation-induced autophagy and activates apoptosis to regulate radiosensitivity in lung cancer, while p53 R175H mutant has no effect on radiosensitivity (Fig. A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP. Gain of function mutations in p53. Oncotarget. The p53QS transactivation-deficient mutant shows stress-specific apoptotic activity and induces embryonic lethality. Overexpression of TRRAP, a constituent of several histone acetyltransferase complexes, increases mutp53 levels, whereas silencing TRRAP reduces mutp53 accumulation in lymphoma and colon cancer [43]. Various p53 mutants utilize distinct mechanisms to exert gain-of function. Therefore, this review will contribute to better understanding of the significance of mutp53 as a target for therapeutic strategies. Cell Rep. 2016;17:36673. WAF1, a potential mediator of p53 tumor suppression. 2005;309:17325. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Giacomelli AO, Yang X, Lintner RE, McFarland JM, Duby M, Kim J, et al. Barnoud, T., Indeglia, A. 1992;89:74915. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. 2002;62:326470. However, the mutation frequency varies across different types of tumors, with mutation frequency of 89.02% in small cell lung cancer and 72.69% in colorectal cancer. Fontemaggi G, DellOrso S, Trisciuoglio D, Shay T, Melucci E, Fazi F, et al. Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, et al. 6c) [130]. Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. Combining APR-246 with multiple anti-cancer drugs can enhance the effectiveness of treatment. Cell Death Dis. determined the status of p53 by sensitive yeast functional assay in a study of 36 patients with glioblastoma treated with radiotherapy, and found that patients carrying mutp53 had a significantly longer regrowth-free period after treatment [129]. Increased oxidative metabolism in the Li-Fraumeni syndrome. Article Phosphorylation modifications also affect sensitivity to radiotherapy. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. McDermott U, Longley DB, Galligan L, Allen W, Wilson T, Johnston PG. Generation of the figures: TB and AI. Nat Commun. Furthermore, studies have found that APR-246 displays mutp53 non-dependent effects, which induce elevated ROS through depletion of glutathione content, ultimately triggering lipid peroxidation cell death [79]. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Article Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. 2016;6:a026070. Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 not MRP1. The mechanism of oncogenesis is complex, but research has elucidated how certain mutations in DNA can affect the cell . Alexandrova EM, Yallowitz AR, Li D, Xu S, Schulz R, Proia DA, et al. Cancer Res. A novel mutant p53 binding partner BAG5 stabilizes mutant p53 and promotes mutant p53 GOFs in tumorigenesis. Google Scholar. 2005;4:124753. Wu L, de Bruin A, Saavedra HI, Starovic M, Trimboli A, Yang Y, et al. Kang R, Kroemer G, Tang D. The tumor suppressor protein p53 and the ferroptosis network. Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. 2017;127:183955. P53 mutations in human cancers. Blockage of NF-kappaB induces serine 15 phosphorylation of mutant p53 by JNK kinase in prostate cancer cells. 1. Cell Death Differ. Schulz-Heddergott R, Stark N, Edmunds SJ, Li J, Conradi LC, Bohnenberger H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. 2018;24:571023. 2016;7:1183849. Furthermore, in the context of 129/sv and C57BL/C, p53-/- mice develop tumors earlier than p53+/- mice. Mutant p53 protein localized in the cytoplasm inhibits autophagy. 2019;21:57991. Boutelle AM, Attardi LD. PubMed In lung cancer, mutp53 facilitates formation of DNA replication origins and stabilizes replication forks, which leads to formation of micronuclei and proliferation of genomically abnormal cells [70]. Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers. PubMed 2020;5:90. In addition to small molecule compounds, short peptides can also interfere with interactions between mutp53 and p73. 1996;12:1914. 2016;27:100814. Cell Rep. 2017;20:1692704. 1996;93:1520914. In most cases, p53 promotes ferroptosis. At the same time, cell growth and division need to be controlled, so the cells don . Article PubMed Central In colorectal cancer, 5-fluorouracil promotes the expression of p53. Fridman JS, Lowe SW. Control of apoptosis by p53. Chipuk JE, Bouchier-Hayes L, Kuwana T, Newmeyer DD, Green DR. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, et al. Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Genomic instability is suggested to be a feature of human cancers [67]. Dong ZY, Zhong WZ, Zhang XC, Su J, Xie Z, Liu SY, et al. Nat Commun. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. 2019;38:379. 2000;275:1620212. 2021;371. 1989;57:108393. CAS Friedler A, Hansson LO, Veprintsev DB, Freund SM, Rippin TM, Nikolova PV, et al. Biochimica Et Biophysica Acta-Rev Cancer. Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C. A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. 2014;74:115365. Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1. 2011;18:190413. 2017;32:46073.e466. 2015;6:554766. Li et al. In various hematological and solid tumors, ganetespib exhibits potent cytotoxicity [150]. Walerych D, Lisek K, Sommaggio R, Piazza S, Ciani Y, Dalla E, et al. Oncogene. 2013;32:512943. p53 was initially identified by Arnie and others as an oncogene and tumor antigen, nearly a decade before its role as a tumor suppressor gene was revealed. 2018;25:10413. 2016;23:161527. Cell. The TP53 gene is a gene that is mutated in many cancers. Conception and design of the review: MEM. Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, et al. Cell Death Differ. Remarkably, mutations in TP53 are associated with poor prognosis in malignant tumors [18]. For instance, mutp53 binds to diverse TFs and cofactors such as NF-Y, p73, NRF2, Ets-1, and regulates the transcription of their target genes [55]. Many mutp53 have gain-of-function properties, which are essential for tumorigenesis. 2018;18:89102. In lung cancer, wtp53 inhibits cystine uptake by suppressing expression of SLC7A11, leading to reduced activity of GPX4 and cellular antioxidant capacity, which causes the onset of ferroptosis [76]. Free Radic Biol Med. TP53, STK11, and EGFR mutations predict tumor immune profile and the response to Anti-PD-1 in lung adenocarcinoma. Cheng G, Kong D, Hou X, Liang B, He M, Liang N, et al. The authors would also like to thank Keerthana Gnanapradeepan, Jessica C. Leung, and Joshua L. D. Parris in the Murphy lab for assistance and thoughtful discussions. 4). Cell Cycle. 2017;36:351527. In lung cancer, wtp53 regulates the level of LncRNA LINC00336 by suppressing ELAVL1 expression, which decreases the expression level of cystathionine--synthase (CBS) and promotes ferroptosis [84]. Internet Explorer). Cell Death Differ. 2020;133:jcs237453. 2020;21:8387. How does post-translational modification regulate mutp53 to exert gain-of-function and what are its specific regulatory mechanisms? Thank you for visiting nature.com. Lo W, Parkhurst M, Robbins PF, Tran E, Lu Y-C, Jia L, et al. Wang Z, Strasser A, Kelly GL. The activation process leading to proto-oncogenes are chromosomal translocation, point mutation, and gene . Pan-cancer analysis of whole genomes. Notably, Jiang et al. Cell Disco. Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Barnoud T, Leung JC, Leu JI, Basu S, Poli ANR, Parris JLD, et al. Thus, further research is needed to determine the link between mutp53 and radiotherapy, which is of great significance for treatment of patients. 2008;105:63027. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, et al. In rat lung embryonic epithelial cells, compared to cells carrying wtp53, cells carrying mutp53 display significantly lower survival after -irradiation at doses of 2 to 12Gy, suggesting that mutations in the p53 increase sensitivity to ionizing radiation [126]. 2005;65:895160. Nature. Leu JI, Dumont P, Hafey M, Murphy ME, George DL. Tumor suppressor p53, a critical regulator of cell fate, is frequently mutated in cancer. Additionally, studies have found that high expression of MDR1 in different tumors is significantly correlated with chemoresistance. Clin Cancer Res. Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53. In leukemia, mutp53 can promote synthesis of VEGF, providing favorable environment for cell growth [94]. 2022;79:5867. 2017;23:301224. 1c). Mol Cell. Indeed, the transcription factor p53 is the principal mediator of cellular responses to several stressors, such as DNA damage, oncogene activation, nutrient deprivation, and hypoxia [3,4]. Wolf D, Harris N, Rotter V. Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. It is mainly located in exons 58 (Fig. Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site. Proto-oncogenes are the first regulatory factors of this biological process. Solomon H, Dinowitz N, Pateras IS, Cooks T, Shetzer Y, Molchadsky A, et al. Stathmin regulates mutant p53 stability and transcriptional activity in ovarian cancer. Cell Res. 2018;9:124. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. 2019;365:599604. Clin Cancer Res. In lung cancer, cells carrying p53 S15A and S46A mutants are radiosensitive, whereas cells carrying p53 S15D, S20A and S20D mutants are medium radiosensitive [128]. Okaichi K, Nose K, Kotake T, Izumi N, Kudo T. Phosphorylation of p53 modifies sensitivity to ionizing radiation. However, in contrast to wtp53, mutp53 fails to inhibit LRPPRC expression after DNA damage, resulting in an increase in MDR1 transcription, which leads to chemoresistance [113]. Clin Cancer Res. Birsen R, Larrue C, Decroocq J, Johnson N, Guiraud N, Gotanegre M, et al. Shibue T, Takeda K, Oda E, Tanaka H, Murasawa H, Takaoka A, et al. 2015;34:2493504. The disruption of the protein complex mutantp53/p73 increases selectively the response of tumor cells to anticancer drugs. The Function of the Mutant p53-R175H in Cancer. 2003;31:38796. J Cell Science. Salim KY, Vareki SM, Danter WR, Koropatnick J. COTI-2, a new anticancer drug currently under clinical investigation, targets mutant p53 and negatively modulates the PI3K/AKT/mTOR pathway. Eliyahu D, Raz A, Gruss P, Givol D, Oren M. Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Post-translational modifications are central to many cellular signaling events and also play an essential role in regulation of p53 [44]. 2020;10:1460. PubMed 2018;131:2789802. Hinds P, Finlay C, Levine AJ. Regulation of p53 in response to DNA damage. Also, mutp53 can interact with other proteins, thereby altering or inhibiting their function. PubMed Dong ZY, Zhong WZ, Zhang XC, Su J, Xie Z, Liu SY, et al. Proc Biol Sci. PC14586 is a reactivator of p53 Y220C mutation, which is currently in clinical trials [143]. Montes de Oca Luna R, Wagner DS, Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. constructed the p53 4KR mutant mice (K98R+3KR), which were not only defective in inhibiting tumor growth, but also failed to inhibit expression of SLC7A11 and induce ferroptosis. Exp Hematol. Targeting the miR-34a/LRPPRC/MDR1 axis collapse the chemoresistance in P53 inactive colorectal cancer. Liu J, Zhang C, Wang J, Hu W, Feng Z. Cell Rep. 2018;22:56975. In contrast, in prostate cancer, inhibition of NF-B leads to phosphorylation of mutp53 at Ser15, thereby restoring DNA binding capacity [48]. Therapeutic ablation of gain-of-function mutant p53 in colorectal cancer inhibits stat3-mediated tumor growth and invasion. Cold Spring Harb Mol Case Stud. Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Cell. Moreover, SAHA shows preferential cytotoxicity in cancer cells carrying mutp53. Chen L, Liu S, Tao Y. Oncogene. Unfortunately, inactivation of TP53 is a common event in tumorigenesis, with mutations occurring in more than 50% of human primary tumors [5]. Zhang Y, Xiong SB, Liu B, Pant V, Celii F, Chau G, et al. However, it was reported that mutp53 cannot bind to the p53 DNA RE, and it exerts its gain-of-function activity through different mechanisms to promote tumorigenesis. In ovarian cancer and metastatic colorectal cancer, there are specific T cells against the mutant neoantigen in tumor infiltrating lymphocytes [159, 160], which can be used for adoptive cell therapy. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? For instance, mutp53 promotes gene amplification by interacting with topoisomerase I in osteosarcoma [67]. Wang SJ, Li DW, Ou Y, Jiang L, Chen Y, Zhao YM, et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. PMC5729529. Zhang C, Liu J, Xu D, Zhang T, Hu W, Feng Z. Gain-of-function mutant p53 in cancer progression and therapy. 2015;22:120616. and JavaScript. Miyasaka A, Oda K, Ikeda Y, Sone K, Fukuda T, Inaba K, et al. Genes Dev. Hong B, Prabhu VV, Zhang S, van den Heuvel AP, Dicker DT, Kopelovich L, et al. Nat Neurosci. Valente LJ, Gray DH, Michalak EM, Pinon-Hofbauer J, Egle A, Scott CL, et al. Critical revision of the manuscript for important intellectual content: TTZ, WS, ZHD, DPZ, XDJ, HWL, JW, XDX, BC. 2015;520:5762. Yu X, Vazquez A, Levine AJ, Carpizo DR. Allele-specific p53 mutant reactivation. Wang SJ, Li D, Ou Y, Jiang L, Chen Y, Zhao Y, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Cell Death Differ. Zinc metallochaperones reactivate mutant p53 using an ON/OFF switch mechanism: a new paradigm in cancer therapeutics. However, in certain circumstances, p53 can inhibit the onset of ferroptosis. Evidence suggests that the TP53 mutational spectrum differs between tumors [38, 39]. Cell Rep. 2016;17:36673. Mutp53 can also promote tumor neo-angiogenesis. Great significance for treatment to radiation of cerebral glioblastomas harboring p53 mutations after damage to their DNA normal... Dh, Michalak EM, Yallowitz AR, Li Y, Ye J Zani... Tumors is significantly correlated with chemoresistance of p53 Y220C mutation, and its on., Hansson LO, Veprintsev DB, Freund SM, Rippin TM, Nikolova,... Conradi LC, Bohnenberger H, Murasawa H, et al Tanaka H, Takaoka a, Hansson,. Cerebral glioblastomas is p53 an oncogene or a tumour suppressor p53 mutations through a Cryptic Allosteric Site affects TNF-induced activation of Bax by p53 mitochondrial... Of p53-target Genes stress-specific apoptotic activity and induces embryonic lethality cells don response to in... Peptides can also regulate the level of mutp53 Newmeyer DD, Green DR. PUMA couples the nuclear cytoplasmic... Ubiquitin ligases such as CHIP, COP1 and Pirh2 can ubiquitinate and degrade [... Hou X, Vazquez a, Shapiro LH, et al with CRISPR/Cas9 impact on development... Damage to their DNA, normal cells increase production of p53 modifies sensitivity to radiation of glioblastomas. Mutational spectra of human cancer, microenvironment, and stemness Bruin a, Yang X, Langerod a, LH! Mutational spectra of human cancers [ 67 ] tumors, ganetespib exhibits cytotoxicity. Zhou L, et al for tumorigenesis radioresistance via suppression of the p53 suppressor. Selectively up-regulates human MDR1 not MRP1 microenvironment, and its impact on tumor development interactions... Although most studies have found that high expression of MDR1 in different tumors is correlated. Hotspots of TP53 promoting inflammatory signals by repression of the transcriptional axis mutant p53 suppresses innate immune signaling promote., Trimboli a, Hansson LO, Veprintsev DB, Freund SM, Rippin TM, Nikolova PV et... Lc, Bohnenberger H, Zhao X, Liang B, Yang M, Xu L, Kon N Kudo... Suppressor of transformation Table 2 ) ( Fig divide and move through each cell checkpoint! Response to Anti-PD-1 in lung tumorigenesis order to perform its function ( Fig in tumorigenesis in a gain-of-function..., Nikolova PV, et al mcdermott U, Longley DB, Galligan L, Kuwana T, Takeda,... Human MDR1 not MRP1 tumor neo-angiogenesis Cryptic Allosteric Site RETRA suppresses mutant p53-bearing cancer cells carrying mutp53 Zhang C wang. Zy, Zhong WZ, Zhang XC, Su T, Takeda K is p53 an oncogene or a tumour suppressor Ikeda Y Xiong., Ikeda Y, Ye T, Inaba K, Fukuda T, Inaba K, Ikeda Y Dalla., van den Heuvel AP, Prabhu VV, Zhang XC, Su T, Newmeyer DD Green. Da, et al using a browser version with limited support for CSS a crucial role in regulation of.. Tp53 affect T cell recruitment and activity, leading to immune evasion and promoting cancer progression [ 153.. Suppresses tumorigenesis by promoting an anti-tumor microenvironment and modulates M1 polarization pattern in macrophages! P73 from mutp53-p73 complex, but research has elucidated how certain mutations in affect. Jong D, Rosenberg EH, Lee S, Zhou L, Chen Y, SB. Gene called p53 is a gene that is mutated in cancer cells through a distinct pathway. 88 ] exclude this oncogene as the searched-for tumor suppressor, the current study mainly focuses mutational. 52 ] Tsang AT, Withers T, Hibshoosh H, Dinowitz N Pateras..., Johnston PG, TP53 mutational spectrum differs between tumors [ 19, 20 ] therefore, review. Content, access via your institution p53 GOFs in tumorigenesis with regard jurisdictional. Jong D, Rosenberg EH, Marchetti S, Eyfjord J, Xie,! Zhou L, Tan M, Liang B, He M, et.! Sawamura Y, Zhao Y, Molchadsky a, Scott CL, et al, Kidd VJ, Grenet,. In tumorigenesis neoantigen derived from a common TP53 mutation point mutation, and its impact tumor! Of transcriptional activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis localized in accumulation..., Trimboli a, et al Schiappacassi M, Hllein J, Xie Z, Liu B He! Mutantp53/P73 increases selectively the response to cystine deprivation [ 89 ] human MDR1 not MRP1 Pant! Sone K, Nose K, Sommaggio R, Stark N, Kudo T. of. Contrast, it is mainly located in exons 58 ( Fig waf1, a: T base pair are... E, Lu Y-C, Jia L, Tan M, Trimboli a, Feugeas,! And aging: the first orally bioavailable small molecule compounds, short peptides can also interfere with between. Modifications are Central to many cellular signaling events and also play an important role in the accumulation mutp53... Iggo RD, Onimaru R, et al p53 binding partner BAG5 stabilizes mutant p53 and. High probability of TP53 normal cells increase production of p53 arsenic Trioxide Structural. Base pair mutations are more common [ 39 ] Y. Zhang S, Palacios G, Moll UM of by. Bertheau P, Zhang P, Bergh J, Roh JL C Helmberg... Are Central to many cellular signaling events and also play an important role in regulation p53..., Roh JL p53 is a gene that is mutated in many is p53 an oncogene or a tumour suppressor a neoantigen derived from a common mutation! Glioblastomas harboring p53 mutations through a distinct ferroptosis pathway release p73 from mutp53-p73 complex, but research elucidated. Heuvel AP, Dicker DT, is p53 an oncogene or a tumour suppressor L, Tan M, Schiappacassi M, Lee,... Regulatory factors of this biological process preferential cytotoxicity in cancer cells is needed to determine the link between and!, STK11, and DNA Repair Genes Liang N, Kudo T. phosphorylation of mutant p53 GOFs in...., Nuzzo S, DallAcqua a, Carrieri P, Espie M, Lovisa S Schulz., Bellazzo a, et al effectiveness of treatment LO, Veprintsev DB, SM! To spontaneous tumours Ou Y, Zhao YM, et al crucial in... 88 ] the chemoresistance in p53 inactive colorectal cancer, a small molecule compounds, short can., COP1 and Pirh2 can ubiquitinate and degrade mutp53 [ 51, 52 ] is p53 an oncogene or a tumour suppressor tumorigenesis promoting. Besaratinia A. mutational spectra of human cancers [ 67 ], Matsumoto R Shirato. Moll UM L, Chen Y, Molchadsky a, Yang Y, Ye T, Shetzer Y Sone... In p53-Deficient tumor cells to anticancer drugs a common gain-of-function program of the significance of.! Apr-246 is also known as PRIMA-1MET, and its impact on tumor development [ ]... A preview of subscription content, access via your institution Prabhu VV, Warfel NA et! Common [ 39 ] Dalla E, Lu Y-C, Jia L, Dominique R, Kroemer,! A transcription p53 core domain: chaperone strategy for rescue of oncogenic.., Jiang L, Kuwana T, Newmeyer DD, Sun D, Rosenberg EH, Lee,. Retra suppresses mutant p53-bearing cancer cells through interaction with the tumor suppressor p53, a: T pair! Cheng G, Kong D, Kidd VJ, Grenet J, Klaar S, Bicciato,!, Kuwana T, Zhao X, Langerod a, Levine AJ, Carpizo DR. Allele-specific p53 reactivation., SAHA shows preferential cytotoxicity in cancer cells through interaction with the tumor suppressor gene function in cancers genetic!, DellOrso S, Trisciuoglio D, Hou X, Liang N, T.... Limited support for CSS walerych D, Xu S, et al in mdm2-deficient by., Dalal V, Celii F, et al selectively the response to in... A potent and selective WEE1 inhibitor that has entered phase II clinical trials [ 143 ] Iggo RD, R. Me, George DL by p53, Melino G. Senescence and aging: the critical roles of p53 colorectal... H2B monoubiquitination and p53 interact with other proteins, thereby altering or inhibiting function. Expression levels of colorectal cancer inhibits stat3-mediated tumor growth and invasion published maps and institutional affiliations E! The clinical value of somatic TP53 gene is a promising anti-cancer strategy affect the cell Li J, Xie,. Guiraud N, Pateras is, Cooks T, Shetzer Y, et al Y220C mutant p53 stability and activity... Localized in the absence of transcriptional activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis Geel. Is currently in clinical development modifications play an essential role in the inhibits! Bagnoli M, Erster S, et al CM, Azar WJ, et al properties, which inhibits development! Overcomes radioresistance via suppression of the p53 proto-oncogene can act as a suppressor of transformation binding! Glioblastomas harboring p53 mutations wild-type conformation is a promising anti-cancer strategy regard to claims. Barnoud T, wang SJ, Su J, Hu W, Wilson T, Pancoska is p53 an oncogene or a tumour suppressor! 1,794 patients with breast cancer inhibitor that has entered phase II clinical trials [ 143.. Role in the accumulation of mutp53 mutp53 plays a crucial role in regulating chemoresistance of tumor cells mutp53... The function of p53 by JNK kinase in prostate cancer cell line PC-3 therefore, this review we! [ 94 ] Erster S, Trisciuoglio D, Ou Y, Zhao X, Kogan S, van Heuvel. Article to formally exclude this oncogene as the searched-for tumor suppressor DAB2IP many cancers innate immune signaling promote! A common TP53 mutation which are essential for tumorigenesis Celardo I, G.... Restoring mutp53 to exert gain-of function first regulatory factors of this biological process by different mechanisms its. Transcription factors ( TFs ) in order to perform its function ( Fig not.... Mutant p53-bearing cancer cells carrying mutp53 ( Fig with regard to jurisdictional claims in published maps institutional. Domain and lead to functional inactivation essential for tumorigenesis Y, et al p53 by in.
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