PARProceedings of Anticancer Research2208-35452208-3553Bio-Byword Scientific Publishing Pty. Ltd.10.26689/par.v8i5.7826ArticleRoles of Mutant TP53 Gene in Cancer Development and Progressionhttps://artdesignp.com/journal/PAR/8/5/10.26689/par.v8i5.7826AbubakarMuhammad,RehmanBaqaur2024852024-09-25TP53 is a tumor suppressor gene that is mutated in most cancer types and has been extensively studied in cancer research. p53 plays a critical role in regulating the expression of target genes and is involved in key processes such as apoptosis, cell cycle regulation, and genomic stability, earning it the title “guardian of the genome.” Numerous studies have demonstrated p53’s influence on and regulation of autophagy, ferroptosis, the tumor microenvironment, and cell metabolism, all of which contribute to tumor suppression. Alterations in p53, specifically mutant p53 (mutp53), not only impair its tumor-suppressing functions but also enhance oncogenic characteristics. Recent data indicate that mutp53 is strongly associated with poor prognosis and advanced cancers, making it an ideal target for the development of novel cancer therapies. This review summarizes the post-translational modifications of p53, the mechanisms of mutp53 accumulation, and its gain-of-function, based on previous findings. Additionally, this review discusses its impact on metabolic homeostasis, ferroptosis, genomic instability, the tumor microenvironment, and cancer stem cells, and highlights recent advancements in mutp53 research.

Feroz W, Sheikh AMA, 2020, Exploring the Multiple Roles of Guardian of the Genome: P53. Egypt J Med Hum Genet, 21: 49. https://doi.org/10.1186/s43042-020-00089-x

Mantovani F, Collavin L, Del Sal G, 2019, Mutant p53 as A Guardian of the Cancer Cell. Cell Death Differ, 26: 199–212. https://doi.org/10.1038/s41418-018-0246-9

Wawrzynow B, Zylicz A, Zylicz M, 2018, Chaperoning the Guardian of the Genome. The Two-Faced Role of Molecular Chaperones in p53 Tumor Suppressor Action. Biochim Biophys Acta Rev Cancer, 1869(2): 161–174. https://doi.org/10.1016/j.bbcan.2017.12.004

Rusin M, 2024, The p53 Protein – Not Only The Guardian of The Genome. Postepy Biochem, 70(1): 71–87. https://doi.org/10.18388/pb.2021_518

Farooq Z, Wani S, Ragunathrao VAB, et al., 2022, p53 Tumor Suppressor: Functional Regulation and Role in Gene Therapy, in Anwar M, Farooq Z, Tauseef M, et al., p53 – A Guardian of the Genome and Beyond. Intech Open. https://doi.org/10.5772/intechopen.105029

Pfister NT, Prives C, 2017, Transcriptional Regulation by Wild-Type and Cancer-Related Mutant Forms of p53. Cold Spring Harb Perspect Med, 7(2): a026054. https://doi.org/10.1101/cshperspect.a026054

Foroutan B, 2023, A Narrative Review of the TP53 and Its Product the p53 Protein. OBM Genetics, 7(3): 185. doi:10.21926/obm.genet.2303185

Reed SM, Quelle DE, 2014, p53 Acetylation: Regulation and Consequences. Cancers (Basel), 7(1): 30–69. https://doi.org/10.3390/cancers7010030

Scoumanne A, Chen X, 2008, Protein Methylation: A New Mechanism of p53 Tumor Suppressor Regulation. Histol Histopathol, 23(9): 1143–1149. https://doi.org/10.14670/HH-23.1143

Tang Y, Zhao W, Chen Y, et al., 2008, Acetylation is Indispensable for p53 Activation. Cell, 133(4): 612–626. https://doi.org/10.1016/j.cell.2008.03.025. Erratum in Cell, 133(7): 1290.

Abdel-Fattah R, Challen C, Griffiths TR, et al., 1998, Alterations of TP53 in Microdissected Transitional Cell Carcinoma of the Human Urinary Bladder: High Frequency of TP53 Accumulation in the Absence of Detected Mutations is Associated with Poor Prognosis. British Journal of Cancer, 77(12): 2230–2238. https://doi.org/10.1038/bjc.1998.371

Olivier M, Hollstein M, Hainaut P, 2010, TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Cold Spring Harb Perspect Biol, 2(1): a001008. https://doi.org/10.1101/cshperspect.a001008

Wang Y, Helland A, Holm R, et al., 2004, TP53 Mutations in Early-Stage Ovarian Carcinoma, Relation to Long-Term Survival. Br J Cancer, 90(3): 678–685. https://doi.org/10.1038/sj.bjc.6601537

Liu J, Zhang C, Zhao Y, et al., 2017, MicroRNA Control of p53. J Cell Biochem, 118(1): 7–14. https://doi.org/10.1002/jcb.25609

Hermeking H, 2012, MicroRNAs in the p53 Network: Micromanagement of Tumour Suppression. Nat Rev Cancer, 12(9): 613–626. https://doi.org/10.1038/nrc3318

He X, He L, Hannon GJ, 2007, The Guardian’s Little Helper: MicroRNAs in The p53 Tumor Suppressor Network. Cancer Res, 67(23): 11099–11101. https://doi.org/10.1158/0008-5472.CAN-07-2672

Ghafouri-Fard S, Shoorei H, Anamag FT, et al., 2020, The Role of Non-Coding RNAs in Controlling Cell Cycle Related Proteins in Cancer Cells. Front Oncol, 10: 608976. https://doi.org/10.3389/fonc.2020.608975

Hu H, Gatti RA, 2011, MicroRNAs: New Players in the DNA Damage Response. Journal of Molecular Cell Biology, 3(3): 151–158. https://doi.org/10.1093/jmcb/mjq042

Pan W, Chai B, Li L, et al., 2023, p53/MicroRNA-34 Axis in Cancer and Beyond. Heliyon, 9(4): e15155. https://doi.org/10.1016/j.heliyon.2023.e15155

Blandino G, Dobbelstein M, 2004, p73 and p63: Why Do We Still Need Them? Cell Cycle, 3(7): 886–894.

Candi E, Agostini M, Melino G, et al., 2014, How The TP53 Family Proteins TP63 and TP73 Contribute to Tumorigenesis: Regulators and Effectors. Hum Mutat, 35(6): 702–714. https://doi.org/10.1002/humu.22523

Flores ER, Sengupta S, Miller JB, et al., 2005, Tumor Predisposition in Mice Mutant for p63 and p73: Evidence for Broader Tumor Suppressor Functions for the p53 Family. Cancer Cell, 7(4): 363–373. https://doi.org/10.1016/j.ccr.2005.02.019

Hernández Borrero LJ, El-Deiry WS, 2021, Tumor Suppressor p53: Biology, Signaling Pathways, and Therapeutic Targeting. Biochim Biophys Acta Rev Cancer, 1876(1): 188556. https://doi.org/10.1016/j.bbcan.2021.188556

Gonfloni S, Caputo V, Iannizzotto V, 2015, P63 in Health and Cancer. Int J Dev Biol, 59(1–3): 87–93. https://doi.org/10.1387/ijdb.150045sg

Pflaum J, Schlosser S, Müller M, 2014, p53 Family and Cellular Stress Responses in Cancer. Front Oncol, 4: 285. https://doi.org/10.3389/fonc.2014.00285

Levrero M, De Laurenzi V, Costanzo A, et al., 2000, The p53/p63/p73 Family of Transcription Factors: Overlapping and Distinct Functions. J Cell Sci, 113(Pt10): 1661–1670. https://doi.org/10.1242/jcs.113.10.1661

Degtjarik O, Golovenko D, Diskin-Posner Y, et al., 2021, Structural Basis of Reactivation of Oncogenic p53 Mutants by A Small Molecule: Methylene Quinuclidinone (MQ). Nat Commun, 12(1): 7057. https://doi.org/10.1038/s41467-021-27142-6

Stiewe T, Haran TE, 2018, How Mutations Shape p53 Interactions with the Genome to Promote Tumorigenesis and Drug Resistance. Drug Resist Updat, 38: 27–43. https://doi.org/10.1016/j.drup.2018.05.001

Vadivel Gnanasundram S, Bonczek O, Wang L, et al., 2021, p53 mRNA Metabolism Links with the DNA Damage Response. Genes (Basel), 12(9): 1446. https://doi.org/10.3390/genes12091446

Meek DW, 2015, Regulation of the p53 Response and Its Relationship to Cancer. Biochem J, 469(3): 325–346. https://doi.org/10.1042/BJ20150517

Nag S, Zhang X, Srivenugopal KS, et al., 2014, Targeting MDM2-p53 Interaction for Cancer Therapy: Are We There Yet? Curr Med Chem, 21(5): 553–574. https://doi.org/10.2174/09298673113206660325

Frum RA, Grossman SR, 2014, Mechanisms of Mutant p53 Stabilization in Cancer. Subcell Biochem, 85: 187–197. https://doi.org/10.1007/978-94-017-9211-0_10

Selivanova G, Wiman KG, 2007, Reactivation of Mutant p53: Molecular Mechanisms and Therapeutic Potential. Oncogene, 26(15): 2243–2254. https://doi.org/10.1038/sj.onc.1210295

Sui X, Jin L, Huang X, et al., 2011, p53 Signaling and Autophagy in Cancer: A Revolutionary Strategy Could Be Developed For Cancer Treatment. Autophagy, 7(6): 565–571. https://doi.org/10.4161/auto.7.6.14073

Mrakovcic M, Fröhlich LF, 2018, p53-Mediated Molecular Control of Autophagy in Tumor Cells. Biomolecules, 8(2): 14. https://doi.org/10.3390/biom8020014

Nguyen TA, Menendez D, Resnick MA, et al., 2014, Mutant TP53 Posttranslational Modifications: Challenges and Opportunities. Hum Mutat, 35(6): 738–755. https://doi.org/10.1002/humu.22506

Kubbutat MHG, Jones SN, Vousden KH, 1997, Regulation of p53 Stability by Mdm2. Nature, 387(6630): 299–303. https://doi.org/10.1038/387299a0

Li D, Marchenko ND, Schulz R, et al., 2011, Functional Inactivation of Endogenous MDM2 and CHIP by HSP90 Causes Aberrant Stabilization of Mutant p53 in Human Cancer Cells. Mol Cancer Res, 9(5): 577–588. https://doi.org/10.1158/1541-7786.MCR-10-0534

Prives C, Hall PA, 1999, The p53 Pathway. Journal of Pathology, 187(1): 112–126.

Levine A, Hu W, Feng Z, 2006, The P53 Pathway: What Questions Remain To Be Explored? Cell Death Differ, 13: 1027–1036. https://doi.org/10.1038/sj.cdd.4401910

Maddocks OD, Vousden KH, 2011, Metabolic Regulation by p53. J Mol Med (Berl), 89(3): 237–245. https://doi.org/10.1007/s00109-011-0735-5. Erratum in J Mol Med, 89(5): 531.

Nagpal I, Yuan ZM, 2021, The Basally Expressed p53-Mediated Homeostatic Function. Front Cell Dev Biol, 9: 775312. https://doi.org/10.3389/fcell.2021.775312

Olovnikov IA, Kravchenko JE, Chumakov PM, 2009, Homeostatic Functions of the p53 Tumor Suppressor: Regulation of Energy Metabolism and Antioxidant Defense. Semin Cancer Biol, 19(1): 32–41. https://doi.org/10.1016/j.semcancer.2008.11.005

Li L, Mao Y, Zhao L, et al., 2019, p53 Regulation of Ammonia Metabolism Through Urea Cycle Controls Polyamine Biosynthesis. Nature, 567(7747): 253–256. https://doi.org/10.1038/s41586-019-0996-7. Erratum in Nature, 569(7758): E10. https://doi.org/10.1038/s41586-019-1121-7

Liu Y, Gu W, 2022, The Complexity of p53-Mediated Metabolic Regulation in Tumor Suppression. Semin Cancer Biol, 85: 4–32. https://doi.org/10.1016/j.semcancer.2021.03.010

Oren M, Rotter V, 2010, Mutant p53 Gain-of-Function in Cancer. Cold Spring Harb Perspect Biol, 2(2): a001107. https://doi.org/10.1101/cshperspect.a001107

Yue X, Zhao Y, Xu Y, et al., 2017, Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy. Journal of Molecular Biology, 429(11): 1595–1606. https://doi.org/10.1016/j.jmb.2017.03.030

Stein Y, Aloni-Grinstein R, Rotter V, 2020, Mutant p53 Oncogenicity: Dominant-Negative or Gain-of-Function? Carcinogenesis, 41(12): 1635–1647. https://doi.org/10.1093/carcin/bgaa117

Chen X, Zhang T, Su W, et al., 2022, Mutant p53 in Cancer: From Molecular Mechanism to Therapeutic Modulation. Cell Death Dis, 13(11): 974. https://doi.org/10.1038/s41419-022-05408-1

Soussi T, Wiman KG, 2007, Shaping Genetic Alterations in Human Cancer: The p53 Mutation Paradigm. Cancer Cell, 12(4): 303–312. https://doi.org/10.1016/j.ccr.2007.10.001

Capuozzo M, Santorsola M, Bocchetti M, et al., 2022, p53: From Fundamental Biology to Clinical Applications in Cancer. Biology (Basel), 11(9): 1325. https://doi.org/10.3390/biology11091325

Kang R, Kroemer G, Tang D, 2019, The Tumor Suppressor Protein p53 and the Ferroptosis Network. Free Radic Biol Med, 133: 162–168. https://doi.org/10.1016/j.freeradbiomed.2018.05.074

Liu Y, Gu W, 2022, p53 in Ferroptosis Regulation: The New Weapon for the Old Guardian. Cell Death Differ, 29(5): 895–910. https://doi.org/10.1038/s41418-022-00943-y

Liu J, Zhang C, Wang J, et al., 2020, The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway. Int J Mol Sci, 21(21): 8387. https://doi.org/10.3390/ijms21218387

Lei G, Zhang Y, Hong T, et al., 2021, Ferroptosis as A Mechanism to Mediate p53 Function in Tumor Radiosensitivity. Oncogene, 40(20): 3533–3547. https://doi.org/10.1038/s41388-021-01790-w

Wang SJ, Li D, Ou Y, et al., 2016, Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression. Cell Rep, 17(2): 366–373. https://doi.org/10.1016/j.celrep.2016.09.022

Xu R, Wang W, Zhang W, 2023, Ferroptosis and The Bidirectional Regulatory Factor p53. Cell Death Discov, 9(1): 197. https://doi.org/10.1038/s41420-023-01517-8

Mola S, 2021, Tumor Associated Macrophages (TAMs) A Pivotal Orchestrator in Cancer-Related Inflammation and A New Important Target in Cancer-Therapy, dissertation, Universita’ degli Studi del Piemonte Orientale “Amedeo Avogadro”.

Shah CA, Allison KH, Garcia RL, et al., 2008, Intratumoral T cells, Tumor-Associated Macrophages, and Regulatory T Cells: Association with p53 Mutations, Circulating Tumor DNA and Survival in Women with Ovarian Cancer. Gynecol Oncol, 109(2): 215–219. https://doi.org/10.1016/j.ygyno.2008.01.010

Bascetta L, 2018, Mutant p53 Alters Tumor Microenvironment by Reprogramming the Cancer Cell Secretome via miR-30d, dissertation, SISSA.

Shetzer Y, Solomon H, Koifman G, et al., 2014, The Paradigm of Mutant p53-Expressing Cancer Stem Cells and Drug Resistance. Carcinogenesis, 35(6): 1196–1208. https://doi.org/10.1093/carcin/bgu073

Molchadsky A, Rotter V, 2017, p53 and Its Mutants on the Slippery Road from Stemness to Carcinogenesis. Carcinogenesis, 38(4): 347–358. https://doi.org/10.1093/carcin/bgw092

Zhao Y, Li Y, Zhang R, et al., 2020, The Role of Erastin in Ferroptosis and Its Prospects in Cancer Therapy. Onco Targets Ther, 13: 5429–5441. https://doi.org/10.2147/OTT.S254995

Babamohamadi M, Babaei E, Ahmed Salih B, et al., 2022, Recent Findings on the Role of Wild-Type and Mutant p53 in Cancer Development and Therapy. Front Mol Biosci, 9: 903075. https://doi.org/10.3389/fmolb.2022.903075

Xiong R, He R, Liu B, et al., 2021, Ferroptosis: A New Promising Target for Lung Cancer Therapy. Oxid Med Cell Longev, 2021: 8457521. https://doi.org/10.1155/2021/8457521

Zhang W, Gai C, Ding D, et al., 2018, Targeted p53 on Small-Molecules-Induced Ferroptosis in Cancers. Front Oncol, 8: 507. https://doi.org/10.3389/fonc.2018.00507

Shi D, Gu W, 2012, Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity. Genes Cancer, 3(3–4): 240–248. https://doi.org/10.1177/1947601912455199

Zhao K, Yang Y, Zhang G, et al., 2018, Regulation of the Mdm2-p53 Pathway by the Ubiquitin E3 Ligase MARCH7. EMBO Rep, 19(2): 305–319. https://doi.org/10.15252/embr.201744465

Ganguli G, Wasylyk B, 2003, p53-Independent Functions of MDM2. Mol Cancer Res, 1(14): 1027–1035.

Ito A, Kawaguchi Y, Lai CH, et al., 2002, MDM2-HDAC1-Mediated Deacetylation of p53 is Required for Its Degradation. EMBO J, 21(22): 6236–6245. https://doi.org/10.1093/emboj/cdf616

Fu X, Yucer N, Liu S, et al., 2010, RFWD3-Mdm2 Ubiquitin Ligase Complex Positively Regulates p53 Stability in Response to DNA Damage. Proc Natl Acad Sci U S A, 107(10): 4579–4584. https://doi.org/10.1073/pnas.0912094107

Brignone C, Bradley KE, Kisselev AF, et al., 2004, A Post-Ubiquitination Role for MDM2 and hHR23A in the p53 Degradation Pathway. Oncogene, 23(23): 4121–4129. https://doi.org/10.1038/sj.onc.1207540

Girnita L, Girnita A, Larsson O, 2003, Mdm2-Dependent Ubiquitination and Degradation of the Insulin-Like Growth Factor 1 Receptor. Proc Natl Acad Sci U S A, 100(14): 8247–8252. https://doi.org/10.1073/pnas.1431613100

Saunders AW, 2016, New Approaches to Stapled Peptides Targeting the p53-MDM2 Interaction, dissertation, University of Edinburgh.

Cromm PM, Spiegel J, Grossmann TN, 2015, Hydrocarbon Stapled Peptides as Modulators of Biological Function. ACS Chem Biol, 10(6): 1362–1375. https://doi.org/10.1021/cb501020r