Journal articles: 'P53; tumour suppressor; cancer'

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S Patil, Priya, Jaydeep N Pol, and Ashalata D Patil. "ROLE OF TUMOUR SUPPRESSOR GENE P53 IN TRIPLE NEGATIVE BREAST CANCER." International Journal of Anatomy and Research 5, no. 4.2 (November 1, 2017): 4585–89. http://dx.doi.org/10.16965/ijar.2017.402.

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HUPP, Ted R., David P. LANE, and Kathryn L. BALL. "Strategies for manipulating the p53 pathway in the treatment of human cancer." Biochemical Journal 352, no. 1 (November 7, 2000): 1–17. http://dx.doi.org/10.1042/bj3520001.

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Human cancer progression is driven in part by the mutation of oncogenes and tumour-suppressor genes which, under selective environmental pressures, give rise to evolving populations of biochemically altered cells with enhanced tumorigenic and metastatic potential. Given that human cancers are biologically and pathologically quite distinct, it has been quite surprising that a common event, perturbation of the p53 pathway, occurs in most if not all types of human cancers. The central role of p53 as a tumour-suppressor protein has fuelled interest in defining its mechanism of function and regulation, determining how its inactivation facilitates cancer progression, and exploring the possibility of restoring p53 function for therapeutic benefit. This review will highlight the key biochemical properties of p53 protein that affect its tumour-suppressor function and the experimental strategies that have been developed for the re-activation of the p53 pathway in cancers.

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Nishikawa, Shigeto, and Tomoo Iwakuma. "Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials." Cancers 15, no. 2 (January 9, 2023): 429. http://dx.doi.org/10.3390/cancers15020429.

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Mutations in the tumor suppressor p53 (p53) promote cancer progression. This is mainly due to loss of function (LOS) as a tumor suppressor, dominant-negative (DN) activities of missense mutant p53 (mutp53) over wild-type p53 (wtp53), and wtp53-independent oncogenic activities of missense mutp53 by interacting with other tumor suppressors or oncogenes (gain of function: GOF). Since p53 mutations occur in ~50% of human cancers and rarely occur in normal tissues, p53 mutations are cancer-specific and ideal therapeutic targets. Approaches to target p53 mutations include (1) restoration or stabilization of wtp53 conformation from missense mutp53, (2) rescue of p53 nonsense mutations, (3) depletion or degradation of mutp53 proteins, and (4) induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 mutations (enhanced YAP/TAZ activities) or deletions (hyperactivated retrotransposons). This review article focuses on clinically available FDA-approved drugs and drugs in clinical trials that target p53 mutations and summarizes their mechanisms of action and activities to suppress cancer progression.

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Steffens Reinhardt, Luiza, Kira Groen, Brianna C. Morten, Jean-Christophe Bourdon, and Kelly A. Avery-Kiejda. "Cytoplasmic p53β Isoforms Are Associated with Worse Disease-Free Survival in Breast Cancer." International Journal of Molecular Sciences 23, no. 12 (June 15, 2022): 6670. http://dx.doi.org/10.3390/ijms23126670.

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TP53 mutations are associated with tumour progression, resistance to therapy and poor prognosis. However, in breast cancer, TP53′s overall mutation frequency is lower than expected (~25%), suggesting that other mechanisms may be responsible for the disruption of this critical tumour suppressor. p53 isoforms are known to enhance or disrupt p53 pathway activity in cell- and context-specific manners. Our previous study revealed that p53 isoform mRNA expression correlates with clinicopathological features and survival in breast cancer and may account for the dysregulation of the p53 pathway in the absence of TP53 mutations. Hence, in this study, the protein expression of p53 isoforms, transactivation domain p53 (TAp53), p53β, Δ40p53, Δ133p53 and Δ160p53 was analysed using immunohistochemistry in a cohort of invasive ductal carcinomas (n = 108). p53 isoforms presented distinct cellular localisation, with some isoforms being expressed in tumour cells and others in infiltrating immune cells. Moreover, high levels of p53β, most likely to be N-terminally truncated β variants, were significantly associated with worse disease-free survival, especially in tumours with wild-type TP53. To the best of our knowledge, this is the first study that analysed the endogenous protein levels of p53 isoforms in a breast cancer cohort. Our findings suggest that p53β may be a useful prognostic marker.

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Lee, Jonathan M., and Alan Bernstein. "Apoptosis, cancer and the p53 tumour suppressor gene." Cancer and Metastasis Reviews 14, no. 2 (June 1995): 149–61. http://dx.doi.org/10.1007/bf00665797.

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Bui, Tung, Yu Gu, Frédéric Ancot, Virginie Sanguin-Gendreau, Dongmei Zuo, and William J. Muller. "Emergence of β1 integrin-deficient breast tumours from dormancy involves both inactivation of p53 and generation of a permissive tumour microenvironment." Oncogene 41, no. 4 (November 15, 2021): 527–37. http://dx.doi.org/10.1038/s41388-021-02107-7.

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AbstractThe molecular and cellular mechanisms underlying mammary tumour dormancy and cancer recurrence are unclear and remain to be elucidated. Here, we report that mammary epithelial-specific disruption of β1 integrin in a murine model of Luminal B human breast cancer drastically impairs tumour growth with proliferation block, apoptosis induction and cellular senescence. β1 integrin-deficient dormant lesions show activation of the tumour suppressor p53, and tumours that circumvent dormancy possess p53 mutation analogous to those in human disease. We further demonstrate that mammary epithelial deletion of p53 in β1 integrin-deficient mice fully rescues tumour dormancy and bypasses cellular senescence. Additionally, recurrent β1 integrin-deficient tumours exhibit fibrosis with increased cancer-associated fibroblast infiltration and extracellular matrix deposition, absent in fast-growing β1 integrin/p53-deficient lesions. Taken together, these observations argue that β1 integrin modulates p53-dependent cellular senescence resulting in tumour dormancy and that pro-tumourigenic stromal cues and intrinsic genetic mutation are required for dormancy exit.

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Ghosh, Anirban, Deborah Stewart, and Greg Matlashewski. "Regulation of Human p53 Activity and Cell Localization by Alternative Splicing." Molecular and Cellular Biology 24, no. 18 (September 15, 2004): 7987–97. http://dx.doi.org/10.1128/mcb.24.18.7987-7997.2004.

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ABSTRACT The development of cancer is a multistep process involving mutations in proto-oncogenes, tumor suppressor genes, and other genes which control cell proliferation, telomere stability, angiogenesis, and other complex traits. Despite this complexity, the cellular pathways controlled by the p53 tumor suppressor protein are compromised in most, if not all, cancers. In normal cells, p53 controls cell proliferation, senescence, and/or mediates apoptosis in response to stress, cell damage, or ectopic oncogene expression, properties which make p53 the prototype tumor suppressor gene. Defining the mechanisms of regulation of p53 activity in normal and tumor cells has therefore been a major priority in cell biology and cancer research. The present study reveals a novel and potent mechanism of p53 regulation originating through alternative splicing of the human p53 gene resulting in the expression of a novel p53 mRNA. This novel p53 mRNA encodes an N-terminally deleted isoform of p53 termed p47. As demonstrated within, p47 was able to effectively suppress p53-mediated transcriptional activity and impair p53-mediated growth suppression. It was possible to select for p53-null cells expressing p47 alone or coexpressing p53 in the presence of p47 but not cells expressing p53 alone. This showed that p47 itself does not suppress cell viability but could control p53-mediated growth suppression. Interestingly, p47 was monoubiquitinated in an Mdm2-independent manner, and this was associated with its export out of the nucleus. In the presence of p47, there was a reduction in Mdm2-mediated polyubiquitination and degradation of p53, and this was also associated with increased monoubiquitination and nuclear export of p53. The expression of p47 through alternative splicing of the p53 gene thus has a major influence over p53 activity at least in part through controlling p53 ubiquitination and cell localization.

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Alhebshi, Hasen, Kun Tian, Lipsita Patnaik, Rebecca Taylor, Pavel Bezecny, Callum Hall, Patricia Anthonia Johanna Muller, et al. "Evaluation of the Role of p53 Tumour Suppressor Posttranslational Modifications and TTC5 Cofactor in Lung Cancer." International Journal of Molecular Sciences 22, no. 24 (December 7, 2021): 13198. http://dx.doi.org/10.3390/ijms222413198.

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Mutations in the p53 tumor suppressor are found in over 50% of cancers. p53 function is controlled through posttranslational modifications and cofactor interactions. In this study, we investigated the posttranslationally modified p53, including p53 acetylated at lysine 382 (K382), p53 phosphorylated at serine 46 (S46), and the p53 cofactor TTC5/STRAP (Tetratricopeptide repeat domain 5/ Stress-responsive activator of p300-TTC5) proteins in lung cancer. Immunohistochemical (IHC) analysis of lung cancer tissues from 250 patients was carried out and the results were correlated with clinicopathological features. Significant associations between total or modified p53 with a higher grade of the tumour and shorter overall survival (OS) probability were detected, suggesting that mutant and/or modified p53 acts as an oncoprotein in these patients. Acetylated at K382 p53 was predominantly nuclear in some samples and cytoplasmic in others. The localization of the K382 acetylated p53 was significantly associated with the gender and grade of the disease. The TTC5 protein levels were significantly associated with the grade, tumor size, and node involvement in a complex manner. SIRT1 expression was evaluated in 50 lung cancer patients and significant positive correlation was found with p53 S46 intensity, whereas negative TTC5 staining was associated with SIRT1 expression. Furthermore, p53 protein levels showed positive association with poor OS, whereas TTC5 protein levels showed positive association with better OS outcome. Overall, our results indicate that an analysis of p53 modified versions together with TTC5 expression, upon testing on a larger sample size of patients, could serve as useful prognostic factors or drug targets for lung cancer treatment.

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Vousden, Karen H. "Functions of p53 in metabolism and invasion." Biochemical Society Transactions 37, no. 3 (May 20, 2009): 511–17. http://dx.doi.org/10.1042/bst0370511.

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The p53 protein is an important tumour suppressor that is inactivated in many human cancers. Understanding how p53 is regulated and the downstream consequences of p53 function is helping us to devise novel therapies based on the reactivation of p53. Such approaches may be useful in the treatment of cancer, but a growing understanding of a role for p53 in other conditions suggests that modulation of p53 may have broader applications.

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Chang, F., S. Syrjänen, A. Tervahauta, and K. Syrjänen. "Tumourigenesis associated with the p53 tumour suppressor gene." British Journal of Cancer 68, no. 4 (October 1993): 653–61. http://dx.doi.org/10.1038/bjc.1993.404.

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Sanz, Gema, Madhurendra Singh, Sylvain Peuget, and Galina Selivanova. "Inhibition of p53 inhibitors: progress, challenges and perspectives." Journal of Molecular Cell Biology 11, no. 7 (July 2019): 586–99. http://dx.doi.org/10.1093/jmcb/mjz075.

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Abstract p53 is the major tumor suppressor and the most frequently inactivated gene in cancer. p53 could be disabled either by mutations or by upstream negative regulators, including, but not limited to MDM2 and MDMX. p53 activity is required for the prevention as well as for the eradication of cancers. Restoration of p53 activity in mouse models leads to the suppression of established tumors of different origin. These findings provide a strong support to the anti-cancer strategy aimed for p53 reactivation. In this review, we summarize recent progress in the development of small molecules, which restore the tumor suppressor function of wild-type p53 and discuss their clinical advance. We discuss different aspects of p53-mediated response, which contribute to suppression of tumors, including non-canonical p53 activities, such as regulation of immune response. While targeting p53 inhibitors is a very promising approach, there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.

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Ohashi, M., F. Kanai, H. Ueno, T. Tanaka, K. Tateishi, T. Kawakami, Y. Koike, et al. "Adenovirus mediated p53 tumour suppressor gene therapy for human gastric cancer cells in vitro and in vivo." Gut 44, no. 3 (March 1, 1999): 366–71. http://dx.doi.org/10.1136/gut.44.3.366.

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BACKGROUND/AIMSGastric cancer is one of the most prevalent forms of cancer in East Asia. Point mutation of the p53 gene has been reported in more than 60% of cases of gastric cancer and can lead to genetic instability and uncontrolled cell proliferation. The purpose of this investigation was to evaluate the potential of p53 gene therapy for gastric cancer.METHODSThe responses of human gastric cancer cell lines, MKN1, MKN7, MKN28, MKN45, and TMK-1, to recombinant adenoviruses encoding wild type p53 (AdCAp53) were analysed in vitro. The efficacy of the AdCAp53 treatment for MKN1 and MKN45 subcutaneous tumours in nude mice was assessed in vivo.RESULTSp53-specific growth inhibition was observed in vitro in two of four gastric cancer cell lines with mutated p53, but not in the wild type p53 cell line. The mechanism of the killing of gastric cancer cells by AdCAp53 was found, by flow cytometric analysis and detection of DNA fragmentation, to be apoptosis. In vivo studies showed that the growth of subcutaneous tumours of p53 mutant MKN1 cells was significantly inhibited by direct injection of AdCAp53, but no significant growth inhibition was detected in the growth of p53 wild type MKN45 tumours.CONCLUSIONSAdenovirus mediated reintroduction of wild type p53 is a potential clinical utility in gene therapy for gastric cancers.

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Pitolli, Consuelo, Ying Wang, Eleonora Candi, Yufang Shi, Gerry Melino, and Ivano Amelio. "p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms." Cancers 11, no. 12 (December 9, 2019): 1983. http://dx.doi.org/10.3390/cancers11121983.

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The tumor suppressor p53 regulates different cellular pathways involved in cell survival, DNA repair, apoptosis, and senescence. However, according to an increasing number of studies, the p53-mediated canonical DNA damage response is dispensable for tumor suppression. p53 is involved in mechanisms regulating many other cellular processes, including metabolism, autophagy, and cell migration and invasion, and these pathways might crucially contribute to its tumor suppressor function. In this review we summarize the canonical and non-canonical functions of p53 in an attempt to provide an overview of the potentially crucial aspects related to its tumor suppressor activity.

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Zhang, Xulin. "MDM2 inhibitors: Targeting p53-MDM2 interaction to anti-cancer." E3S Web of Conferences 308 (2021): 02015. http://dx.doi.org/10.1051/e3sconf/202130802015.

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P53 is a recognized tumor suppressor gene, which mainly depends on the activity of its transfer factor to realize the tumor suppressor effect. Mouse two-minute 2 (MDM2) is an important inhibitor of p53. When combined with MDM2, the activity of p53 will be reduced, and the anti-cancer effect will be weakened. According to the mechanism between p53 and MDM2, researchers focus on the inhibitors to inhibit their binding. Through a large number of drug screening methods and means, this article has found many new inhibitors of p53-MDM2 interaction, most of which are still in the clinical research stage. Specifically, we classify the drugs based on their different action mechanisms. Firstly, some drugs combine with MDM2 to inhibit the p53-MDM2 interaction. They are Siremadlin (NVP-HDM201), RG7112, and NVP-CGM09. While some act on p53, they rely on their induction of p53 signalling and inhibition of tumour cell proliferation in p53 wild-type tumor cell lines, like MK-8242 and KRT-232(AMG-232). What’s more, one inhibitor’s action bases on P53 and MDM2 in T cells is APG-115. And last but not least, there are also several drugs that stable tumor suppressor TP53, leading to p53 activation and inducing cell cycle arrest and apoptosis, they are Idasanutlin (RG7388) and Milademetan (DS-3032/RAIN-32). Furthermore, clinical studies are finding that monotherapy does not deliver a powerful therapeutic effect. Various combination strategies are being explored with MDM2 inhibitors preclinically and in the clinic. This article will talk about some specific combinations: APG-115 combine with immune checkpoint inhibitor PD-1/PD-L1, MDM2 inhibitors combine with BCL-2 inhibitors, anti-CD20 therapeutic antibodies, and the last, combine with alkylating agents.

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Moureau, Sylvie, Janna Luessing, Emma Christina Harte, Muriel Voisin, and Noel Francis Lowndes. "A role for the p53 tumour suppressor in regulating the balance between homologous recombination and non-homologous end joining." Open Biology 6, no. 9 (September 2016): 160225. http://dx.doi.org/10.1098/rsob.160225.

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Loss of p53, a transcription factor activated by cellular stress, is a frequent event in cancer. The role of p53 in tumour suppression is largely attributed to cell fate decisions. Here, we provide evidence supporting a novel role for p53 in the regulation of DNA double-strand break (DSB) repair pathway choice. 53BP1, another tumour suppressor, was initially identified as p53 Binding Protein 1, and has been shown to inhibit DNA end resection, thereby stimulating non-homologous end joining (NHEJ). Yet another tumour suppressor, BRCA1, reciprocally promotes end resection and homologous recombination (HR). Here, we show that in both human and mouse cells, the absence of p53 results in impaired 53BP1 focal recruitment to sites of DNA damage induced by ionizing radiation. This effect is largely independent of cell cycle phase and the extent of DNA damage. In p53-deficient cells, diminished localization of 53BP1 is accompanied by a reciprocal increase in BRCA1 recruitment to DSBs. Consistent with these findings, we demonstrate that DSB repair via NHEJ is abrogated, while repair via homology-directed repair (HDR) is stimulated. Overall, we propose that in addition to its role as an ‘effector’ protein in the DNA damage response, p53 plays a role in the regulation of DSB repair pathway choice.

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Rozenberg, Julian M., Svetlana Zvereva, Alexandra Dalina, Igor Blatov, Ilya Zubarev, Daniil Luppov, Alexander Bessmertnyi, et al. "Dual Role of p73 in Cancer Microenvironment and DNA Damage Response." Cells 10, no. 12 (December 13, 2021): 3516. http://dx.doi.org/10.3390/cells10123516.

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Understanding the mechanisms that regulate cancer progression is pivotal for the development of new therapies. Although p53 is mutated in half of human cancers, its family member p73 is not. At the same time, isoforms of p73 are often overexpressed in cancers and p73 can overtake many p53 functions to kill abnormal cells. According to the latest studies, while p73 represses epithelial–mesenchymal transition and metastasis, it can also promote tumour growth by modulating crosstalk between cancer and immune cells in the tumor microenvironment, M2 macrophage polarisation, Th2 T-cell differentiation, and angiogenesis. Thus, p73 likely plays a dual role as a tumor suppressor by regulating apoptosis in response to genotoxic stress or as an oncoprotein by promoting the immunosuppressive environment and immune cell differentiation.

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Capuozzo, Maurizio, Mariachiara Santorsola, Marco Bocchetti, Francesco Perri, Marco Cascella, Vincenza Granata, Venere Celotto, et al. "p53: From Fundamental Biology to Clinical Applications in Cancer." Biology 11, no. 9 (September 6, 2022): 1325. http://dx.doi.org/10.3390/biology11091325.

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p53 tumour suppressor gene is our major barrier against neoplastic transformation. It is involved in many cellular functions, including cell cycle arrest, senescence, DNA repair, apoptosis, autophagy, cell metabolism, ferroptosis, immune system regulation, generation of reactive oxygen species, mitochondrial function, global regulation of gene expression, miRNAs, etc. Its crucial importance is denounced by the high percentage of amino acid sequence identity between very different species (Homo sapiens, Drosophila melanogaster, Rattus norvegicus, Danio rerio, Canis lupus familiaris, Gekko japonicus). Many of its activities allowed life on Earth (e.g., repair from radiation-induced DNA damage) and directly contribute to its tumour suppressor function. In this review, we provide paramount information on p53, from its discovery, which is an interesting paradigm of science evolution, to potential clinical applications in anti-cancer treatment. The description of the fundamental biology of p53 is enriched by specific information on the structure and function of the protein as well by tumour/host evolutionistic perspectives of its role.

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Lai, Dulcie, Stacy Visser-Grieve, and Xiaolong Yang. "Tumour suppressor genes in chemotherapeutic drug response." Bioscience Reports 32, no. 4 (April 23, 2012): 361–74. http://dx.doi.org/10.1042/bsr20110125.

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Since cancer is one of the leading causes of death worldwide, there is an urgent need to find better treatments. Currently, the use of chemotherapeutics remains the predominant option for cancer therapy. However, one of the major obstacles for successful cancer therapy using these chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. Therefore identification of genes involved in chemotherapeutic response is critical for predicting tumour response and treating drug-resistant cancer patients. A group of genes commonly lost or inactivated are tumour suppressor genes, which can promote the initiation and progression of cancer through regulation of various biological processes such as cell proliferation, cell death and cell migration/invasion. Recently, mounting evidence suggests that these tumour suppressor genes also play a very important role in the response of cancers to a variety of chemotherapeutic drugs. In the present review, we will provide a comprehensive overview on how major tumour suppressor genes [Rb (retinoblastoma), p53 family, cyclin-dependent kinase inhibitors, BRCA1 (breast-cancer susceptibility gene 1), PTEN (phosphatase and tensin homologue deleted on chromosome 10), Hippo pathway, etc.] are involved in chemotherapeutic drug response and discuss their applications in predicting the clinical outcome of chemotherapy for cancer patients. We also propose that tumour suppressor genes are critical chemotherapeutic targets for the successful treatment of drug-resistant cancer patients in future applications.

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Attardi, Laura D., Brittany M. Flowers, Kathryn Hanson, Abigail S. Mulligan, Sofia Ferreira, Sohinee Bhattacharyya, Hannes Vogel, Laura D. Wood, and Mara Sherman. "Abstract A051: Understanding the Arf-p53 axis in PDAC suppression." Cancer Research 82, no. 22_Supplement (November 15, 2022): A051. http://dx.doi.org/10.1158/1538-7445.panca22-a051.

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Abstract Understanding the gene regulatory networks that contribute to PDAC initiation and progression is critical for improving early detection and more effectively treating this disease. Activating mutations in KRAS are often accompanied by mutations in the TP53, CDKN2A, and SMAD4 tumor suppressor genes in ~72%, 30%, and 32% of PDAC cases (Raphael et al. 2017). Understanding the consequences of deletion of individual tumor suppressor genes can delineate specific genotype-phenotype correlations that can provide new clinical insights. Using a genetically engineered mouse PDAC model based on KrasG12D expression and tumor suppressor gene inactivation through Ptf1aCreER expression in adult acinar cells, we showed previously that p53 deletion or point mutation dramatically accelerates PDAC relative to mice with intact p53. To understand tumor evolution in mice with different p53 statuses, we analyzed the transcriptomic profiles of PDACs developing with intact or mutant p53 by spatial transcriptomics and both bulk and single cell RNA-sequencing. These experiments have provided insight into the pathways that become dysregulated as PDAC develops in the context of different p53 alleles. In addition, as oncogenic signals trigger p53 stabilization via the p19ARF (ARF) protein in some contexts, we sought to determine whether ARF acts upstream of p53 in PDAC suppression. Indeed, the frequent deletion of the CDKN2A locus, which encodes both the ARF and p16INK4A (p16) tumor suppressor genes, suggests the importance of both these genes in suppressing PDAC, but the specific role of ARF in PDAC suppression has not been tested. Using mouse models to definitively interrogate the importance of ARF in suppressing PDAC, we found that Arf inactivation promotes KrasG12D-driven PDAC, and with a latency similar to p53 inactivation. Interestingly, concurrent inactivation of both p53 and Arf accelerated oncogenic KRAS-driven PDAC development relative to p53 inactivation alone, suggesting a p53-independent role for ARF in PDAC suppression. Transcriptomic profiling of tumors from these mice revealed both p53-dependent and p53-independent programs of ARF-mediated tumor suppression, which provides insight into how tumors develop in the absence of ARF. Characterization of the immune and fibroblast components of the tumor microenvironment in tumors with intact tumor suppressors, p53 deficiency, Arf deficiency and combined p53;Arf deficiency reveals genotype-dependent differences, including different CAF profiles observed in tumors of different genotypes. Ongoing analysis of human PDAC will help to further parse the roles of ARF and p16 in human pancreatic cancer development. Together, these studies will help to illuminate how p53 and Arf inactivation contribute to cancer cell evolution and crosstalk with the tumor microenvironment during PDAC development, understanding with potential for improving clinical interventions in PDAC. Citation Format: Laura D. Attardi, Brittany M. Flowers, Kathryn Hanson, Abigail S. Mulligan, Sofia Ferreira, Sohinee Bhattacharyya, Hannes Vogel, Laura D. Wood, Mara Sherman. Understanding the Arf-p53 axis in PDAC suppression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A051.

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Engin, Ayse, Bensu Karahalil, Ali Karakaya, and Atilla Engin. "Association Between XRCC1 ARG399GLN and P53 ARG72PRO Polymorphisms and the Risk of Gastric and Colorectal Cancer in Turkish Population." Archives of Industrial Hygiene and Toxicology 62, no. 3 (September 1, 2011): 207–14. http://dx.doi.org/10.2478/10004-1254-62-2011-2098.

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Association Between XRCC1 ARG399GLN and P53 ARG72PRO Polymorphisms and the Risk of Gastric and Colorectal Cancer in Turkish PopulationGastric cancer is one of the most common cancers of the gastrointestinal system, and its overall five-year survival rate is still 15 % to 20 %, as it can mostly be diagnosed at an advanced stage. On the other hand, although colorectal cancer has a rather good prognosis, mortality is one half that of the incidence.As carcinogenesis is believed to involve reactive radicals that cause DNA adduct formation, impaired repair activity, and weakened tumour suppression, it would help to understand the role of the polymorphisms of nucleotide excision repair enzyme XRCC1 and of tumour suppressor gene p53 in gastric and colorectal cancers. Our study included 94 gastric cancer patients, 96 colorectal cancer patients, and 108 cancer-free individuals as control with the aim to see if there was an association between XRCC1 Arg399Gln and p53 Arg72Pro polymorphisms and cancer susceptibility. DNA was extracted from peripheral blood cells and genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism. Polymorphism p53 Arg72Pro was not associated with either gastric or colorectal carcinoma, while XRCC1 Arg399Gln was not associated with the increased risk of colorectal cancer. However, XRCC1 homozygous Gln allele at codon 399 was associated with 2.54 times higher risk of gastric cancer.

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Devor, Eric J., Brandon M. Schickling, Jace R. Lapierre, David P. Bender, Jesus Gonzalez-Bosquet, and Kimberly K. Leslie. "The Synthetic Curcumin Analog HO-3867 Rescues Suppression of PLAC1 Expression in Ovarian Cancer Cells." Pharmaceuticals 14, no. 9 (September 21, 2021): 942. http://dx.doi.org/10.3390/ph14090942.

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Elevated expression of placenta-specific protein 1 (PLAC1) is associated with the increased proliferation and invasiveness of a variety of human cancers, including ovarian cancer. Recent studies have shown that the tumor suppressor p53 directly suppresses PLAC1 transcription. However, mutations in p53 lead to the loss of PLAC1 transcriptional suppression. Small molecules that structurally convert mutant p53 proteins to wild-type conformations are emerging. Our objective was to determine whether the restoration of the wild-type function of mutated p53 could rescue PLAC1 transcriptional suppression in tumors harboring certain TP53 mutations. Ovarian cancer cells OVCAR3 and ES-2, both harboring TP53 missense mutations, were treated with the p53 reactivator HO-3867. Treatment with HO-3867 successfully rescued PLAC1 transcriptional suppression. In addition, cell proliferation was inhibited and cell death through apoptosis was increased in both cell lines. We conclude that the use of HO-3867 as an adjuvant to conventional therapeutics in ovarian cancers harboring TP53 missense mutations could improve patient outcomes. Validation of this conclusion must, however, come from an appropriately designed clinical trial.

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Bálint, É., and K. H. Vousden. "Activation and activities of the p53 tumour suppressor protein." British Journal of Cancer 85, no. 12 (December 2001): 1813–23. http://dx.doi.org/10.1054/bjoc.2001.2128.

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Suzuki, Kazufumi, and Hisahiro Matsubara. "Recent Advances in p53 Research and Cancer Treatment." Journal of Biomedicine and Biotechnology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/978312.

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TP53, encoding p53, is one of the most famous tumor suppressor genes. The majority of human cancers demonstrate the inactivation of the p53 pathway. Mutant p53 not only, no longer, functions as a tumor suppressor but can also exert tumor-promoting effects. The basic function of p53 is to respond to cellular stress. We herein review the recent advances in p53 research and focus on apoptosis, cell cycle arrest, and senescence in response to stress. We also review the clinical applications of p53-based therapy for human cancer.

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Merabet, Assia, Hellen Houlleberghs, Kate Maclagan, Ester Akanho, Tam T. T. Bui, Bruno Pagano, Alex F. Drake, Franca Fraternali, and Penka V. Nikolova. "Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights." Biochemical Journal 427, no. 2 (March 29, 2010): 225–36. http://dx.doi.org/10.1042/bj20091888.

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To assess the potential of mutations from the L1 loop of the tumour suppressor p53 as second-site suppressors, the effect of H115N and S116M on the p53 ‘hot spot’ mutations has been investigated using the double-mutant approach. The effects of these two mutants on the p53 hot spots in terms of thermal stability and DNA binding were evaluated. The results show that: (i) the p53 mutants H115N and S116M are thermally more stable than wild-type p53; (ii) H115N but not S116M is capable of rescuing the DNA binding of one of the most frequent p53 mutants in cancer, R248Q, as shown by binding of R248Q/H115N to gadd45 (the promoter of a gene involved in cell-cycle arrest); (iii) the double mutant R248Q/H115N is more stable than wild-type p53; (iv) the effect of H115N as a second-site suppressor to restore DNA-binding activity is specific to R248Q, but not to R248W; (v) molecular-dynamics simulations indicate that R248Q/H115N has a conformation similar to wild-type p53, which is distinct from that of R248Q. These findings could be exploited in designing strategies for cancer therapy to identify molecules that could mimic the effect of H115N in restoring function to oncogenic p53 mutants.

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Macgeoch, Catriona, Diana M. Barnes, Julia A. Newton, Shehla Mohammed, Shirley V. Hodgson, Mun Ng, D. Timothy Bishop, and Nigel K. Spurr. "p53 Protein Detected By Immunohistochemical Staining is Not Always Mutant." Disease Markers 11, no. 5-6 (1993): 239–50. http://dx.doi.org/10.1155/1993/480686.

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The expression of the tumour suppressor gene p53 was analyzed in a variety of human solid tumours by immunohistochemistry and direct DNA sequencing. Positive nuclear staining using a panel of anti-p53 antibodies was used to select tumours for further genetic analysis. Using PCR amplification followed by immobilization onto magnetic beads and direct sequencing, we sequenced exons 5-9 of the p53 gene fro m 9 melanomas, 8 nasopharyngeal carcinomas, 16 sporadic breast carcinomas and 11 patients from familial breast cancer families. No sequence alterations of the p53 gene were detected in either the melanoma or nasopharyngeal tumours and only 19% of the primary breast carcinomas showed a variant band indicative of a mutation. Our results indicate firstly that p53 mutations are not generally involved in the tumour types studied and secondly the data emphasize the disparity encountered when attempting to correlate p53 immunohistochemical positivity with mutations within the p53 gene.

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Theobald, Matthias, and Rienk Offringa. "Anti-p53-directed immunotherapy of malignant disease." Expert Reviews in Molecular Medicine 5, no. 11 (March 28, 2003): 1–13. http://dx.doi.org/10.1017/s1462399403006173.

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Mutation and aberrant expression of the p53 tumour suppressor protein are the most frequent molecular alterations in human malignancy. Peptides derived from the p53 protein and presented by major histocompatibility complex molecules for T-cell recognition could serve as universal tumour-associated antigens for cancer immunotherapy. Because p53 normally functions as a ubiquitously expressed self-protein, controlling cell-cycle progression and apoptosis, it also represents a paradigm target molecule for tumour-reactive yet self-antigen-specific T cells. Tailoring p53-based cancer immunotherapy thus requires both interference with p53-specific self-tolerance and induction of the entire repertoire of p53-reactive T cells. Transferring selected T-cell receptor genes into human T cells offers a novel and appealing strategy to meet these requirements.

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Malaguarnera, Roberta, Angelo Mandarino, Emanuela Mazzon, Veronica Vella, Piero Gangemi, Carlo Vancheri, Paolo Vigneri, Alessandra Aloisi, Riccardo Vigneri, and Francesco Frasca. "The p53-homologue p63 may promote thyroid cancer progression." Endocrine-Related Cancer 12, no. 4 (December 2005): 953–71. http://dx.doi.org/10.1677/erc.1.00968.

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Inactivation of p53 and p73 is known to promote thyroid cancer progression. We now describe p63 expression and function in human thyroid cancer. TAp63α is expressed in most thyroid cancer specimens and cell lines, but not in normal thyrocytes. However, in thyroid cancer cells TAp63α fails to induce the target genes (p21Cip1, Bax, MDM2) and, as a consequence, cell cycle arrest and apoptosis occur. Moreover, TAp63α antagonizes the effect of p53 on target genes, cell viability and foci formation, and p63 gene silencing by small interfering (si) RNA results in improved p53 activity. This unusual effect of TAp63α depends on the protein C-terminus, since TAp63β and TAp63γ isoforms, which have a different arrangement of their C-terminus, are still able to induce the target genes and to exert tumour-restraining effects in thyroid cancer cells. Our data outline the existence of a complex network among p53 family members, where TAp63α may promote thyroid tumour progression by inactivating the tumour suppressor activity of p53.

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Oleinik, Natalia V., Natalia I. Krupenko, David G. Priest, and Sergey A. Krupenko. "Cancer cells activate p53 in response to 10-formyltetrahydrofolate dehydrogenase expression." Biochemical Journal 391, no. 3 (October 25, 2005): 503–11. http://dx.doi.org/10.1042/bj20050533.

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A folate enzyme, FDH (10-formyltetrahydrofolate dehydrogenase; EC 1.5.1.6), is not a typical tumour suppressor, but it has two basic characteristics of one, i.e. it is down-regulated in tumours and its expression is selectively cytotoxic to cancer cells. We have recently shown that ectopic expression of FDH in A549 lung cancer cells induces G1 arrest and apoptosis that was accompanied by elevation of p53 and its downstream target, p21. It was not known, however, whether FDH-induced apoptosis is p53-dependent or not. In the present study, we report that FDH-induced suppressor effects are strictly p53-dependent in A549 cells. Both knockdown of p53 using an RNAi (RNA interference) approach and disabling of p53 function by dominant-negative inhibition with R175H mutant p53 prevented FDH-induced cytotoxicity in these cells. Ablation of the FDH-suppressor effect is associated with an inability to activate apoptosis in the absence of functional p53. We have also shown that FDH elevation results in p53 phosphorylation at Ser-6 and Ser-20 in the p53 transactivation domain, and Ser-392 in the C-terminal domain, but only Ser-6 is strictly required to mediate FDH effects. Also, translocation of p53 to the nuclei and expression of the pro-apoptotic protein PUMA (Bcl2 binding component 3) was observed after induction of FDH expression. Elevation of FDH in p53 functional HCT116 cells induced strong growth inhibition, while growth of p53-deficient HCT116 cells was unaffected. This implies that activation of p53-dependent pathways is a general downstream mechanism in response to induction of FDH expression in p53 functional cancer cells.

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Shi, Y.-F., X. Xie, C.-L. Zhao, D.-F. Ye, S.-M. Lu, JJ Hor, and CC Pao. "Lack of mutation in tumour-suppressor gene p53 in gestational trophoblastic tumours." British Journal of Cancer 73, no. 10 (May 1996): 1216–19. http://dx.doi.org/10.1038/bjc.1996.233.

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Seo, Jinho, Daehyeon Seong, Seung Ri Lee, Doo-Byoung Oh, and Jaewhan Song. "Post-Translational Regulation of ARF: Perspective in Cancer." Biomolecules 10, no. 8 (August 4, 2020): 1143. http://dx.doi.org/10.3390/biom10081143.

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Tumorigenesis can be induced by various stresses that cause aberrant DNA mutations and unhindered cell proliferation. Under such conditions, normal cells autonomously induce defense mechanisms, thereby stimulating tumor suppressor activation. ARF, encoded by the CDKN2a locus, is one of the most frequently mutated or deleted tumor suppressors in human cancer. The safeguard roles of ARF in tumorigenesis are mainly mediated via the MDM2-p53 axis, which plays a prominent role in tumor suppression. Under normal conditions, low p53 expression is stringently regulated by its target gene, MDM2 E3 ligase, which induces p53 degradation in a ubiquitin-proteasome-dependent manner. Oncogenic signals induced by MYC, RAS, and E2Fs trap MDM2 in the inhibited state by inducing ARF expression as a safeguard measure, thereby activating the tumor-suppressive function of p53. In addition to the MDM2-p53 axis, ARF can also interact with diverse proteins and regulate various cellular functions, such as cellular senescence, apoptosis, and anoikis, in a p53-independent manner. As the evidence indicating ARF as a key tumor suppressor has been accumulated, there is growing evidence that ARF is sophisticatedly fine-tuned by the diverse factors through transcriptional and post-translational regulatory mechanisms. In this review, we mainly focused on how cancer cells employ transcriptional and post-translational regulatory mechanisms to manipulate ARF activities to circumvent the tumor-suppressive function of ARF. We further discussed the clinical implications of ARF in human cancer.

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Witharana, Chamindri, and RanmuniBhagya Lakshani Dharmawickreme. "Bacterial protein azurin and tumour suppressor p53 in cancer regression." Advances in Human Biology 11, no. 2 (2021): 147. http://dx.doi.org/10.4103/aihb.aihb_69_20.

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Langdon, J. D., and M. Partridge. "Expression of the tumour suppressor gene p53 in oral cancer." British Journal of Oral and Maxillofacial Surgery 30, no. 4 (August 1992): 214–20. http://dx.doi.org/10.1016/0266-4356(92)90263-i.

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Hengstermann, Arnd, Michael A. D'silva, Petric Kuballa, Karin Butz, Felix Hoppe-Seyler, and Martin Scheffner. "Growth Suppression Induced by Downregulation of E6-AP Expression in Human Papillomavirus-Positive Cancer Cell Lines Depends on p53." Journal of Virology 79, no. 14 (July 2005): 9296–300. http://dx.doi.org/10.1128/jvi.79.14.9296-9300.2005.

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ABSTRACT The ubiquitin-protein ligase E6-AP is utilized by the E6 oncoprotein of human papillomaviruses (HPVs) associated with cervical cancer to target the tumor suppressor p53 for degradation. Here, we report that downregulation of E6-AP expression by RNA interference results in both the accumulation of p53 and growth suppression of the HPV-positive cervical cancer cell lines HeLa and SiHa. In addition, HeLa cells, in which p53 expression was suppressed by RNA interference, are significantly less sensitive to the downregulation of E6-AP expression with respect to growth suppression than parental HeLa cells. These data indicate that the anti-growth-suppressive properties of E6-AP in HPV-positive cells depend on its ability to induce p53 degradation.

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Verma, Poonam, Amit Ghosh, Manisha Ray, and Saurav Sarkar. "Lauric Acid Modulates Cancer-Associated microRNA Expression and Inhibits the Growth of the Cancer Cell." Anti-Cancer Agents in Medicinal Chemistry 20, no. 7 (July 3, 2020): 834–44. http://dx.doi.org/10.2174/1871520620666200310091719.

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Background: microRNAs are known to regulate various protein-coding gene expression posttranscriptionally. Fatty acids are cell membrane constituents and are also known to influence the biological activities of the cells like signal transduction, growth and differentiation of the cells, apoptosis induction, and other physiological functions. In our experiments, we used lauric acid to analyse its effects on human cancerous cell lines. Objective: Our objective was to speculate the miRNA expression profile in lauric acid treated and untreated cancerous cell lines and further study the metabolic pathways of the targeted tumour suppressor and oncogenes. Methods: The KB cells and HepG2 cells were treated with lauric acid and miRNA was isolated and the expression of tumour suppressor and oncogenic miRNA was measured by quantitative PCR. The untreated cells were used as control. The metabolic pathways of the target tumour suppressor and oncogenes were examined by GeneMANIA software. Results: Interestingly, the lauric acid treatment suppresses the expression of oncogenic miRNA and significantly upregulated the expression of some tumour suppressor miRNAs. GeneMANIA metabolic pathway revealed that the upregulated tumour suppressor miRNAs regulate several cancer-associated pathways such as DNA damage, signal transduction p53 class mediator, stem cell differentiation, cell growth, cell cycle phase transition, apoptotic signalling pathway, cellular response to stress and radiation, etc. whereas oncogenic miRNAs regulate the cancer-associated pathway like cell cycle phase transition, apoptotic signalling pathway, cell growth, response to oxidative stress, immune response activating cell surface protein signalling pathway, cyclin-dependent protein kinase activity, epidermal growth factor receptor signalling pathways, etc. Conclusion: In our study, we found that lauric acid works as an anticancer agent by altering the expression of miRNAs.

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Chang, F., S. Syrjänen, and K. Syrjänen. "Implications of the p53 tumor-suppressor gene in clinical oncology." Journal of Clinical Oncology 13, no. 4 (April 1995): 1009–22. http://dx.doi.org/10.1200/jco.1995.13.4.1009.

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PURPOSE The p53 gene encompasses 16 to 20 kb of DNA on the short arm of human chromosome 17. It encodes for a 393-amino acid nuclear phosphoprotein involved in cell-cycle control. Loss of normal p53 function is associated with cell transformation in vitro and development of neoplasms in vivo. During the past few years, the dramatic progress in the molecular biology of p53 has raised the exciting prospect for cancer management. The purpose of this review is to assess the potential role of p53 in clinical oncology. DESIGN Data on the alterations in the p53 gene in human cancers, with special emphasis on the clinical implications of changes in the p53 gene in the pathogenesis, diagnosis, prognosis, and therapy of human cancers, are summarized in this review. RESULTS AND CONCLUSION Current evidence suggests that abrogation of normal p53 pathway is a common feature in human cancers, and it appears to be a critical step in the pathogenesis and progression of tumors. Analysis of p53 function and mutations in human cancers may lead to identification of the precise nature of the carcinogenic damage in human tissues. These laboratory investigations and biologic findings have raised the possibility to screen patients at increased risk for cancer, aid the diagnosis made by traditional methods, assess the prognosis of individual cancer patient, design treatment protocols, and test the response to therapeutic agents.

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Abraham, Aswin G., and Eric O’Neill. "PI3K/Akt-mediated regulation of p53 in cancer." Biochemical Society Transactions 42, no. 4 (August 1, 2014): 798–803. http://dx.doi.org/10.1042/bst20140070.

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Mutations activating the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway and inactivating the TP53 tumour-suppressor gene are common mechanisms that cancer cells require to proliferate and escape pre-programmed cell death. In a well-described mechanism, Akt mediates negative control of p53 levels through enhancing MDM2 (murine double minute 2)-mediated targeting of p53 for degradation. Accumulating evidence is beginning to suggest that, in certain circumstances, PTEN (phosphatase and tensin homologue deleted on chromosome 10)/PI3K/Akt also promotes p53 translation and protein stability, suggesting that additional mechanisms may be involved in the Akt-mediated regulation of p53 in tumours. In the present article, we discuss these aspects in the light of clinical PI3K/Akt inhibitors, where information regarding the effect on p53 activity will be a crucial factor that will undoubtedly influence therapeutic efficacy.

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Miyajima, Chiharu, Yurika Hayakawa, Yasumichi Inoue, Mai Nagasaka, and Hidetoshi Hayashi. "HMG-CoA Reductase Inhibitor Statins Activate the Transcriptional Activity of p53 by Regulating the Expression of TAZ." Pharmaceuticals 15, no. 8 (August 17, 2022): 1015. http://dx.doi.org/10.3390/ph15081015.

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Transcriptional coactivator with PDZ-binding motif (TAZ) is a downstream transcriptional regulator of the Hippo pathway that controls cell growth and differentiation. The aberrant activation of TAZ correlates with a poor prognosis in human cancers, such as breast and colon cancers. We previously demonstrated that TAZ inhibited the tumor suppressor functions of p53 and enhanced cell proliferation. Statins, which are used to treat dyslipidemia, have been reported to suppress the activity of TAZ and exert anti-tumor effects. In the present study, we focused on the regulation of p53 functions by TAZ and investigated whether statins modulate these functions via TAZ. The results obtained suggest that statins, such as simvastatin and fluvastatin, activated the transcriptional function of p53 by suppressing TAZ protein expression. Furthermore, co-treatment with simvastatin and anti-tumor agents that cooperatively activate p53 suppressed cancer cell survival. These results indicate a useful mechanism by which statins enhance the effects of anti-tumor agents through the activation of p53 and may represent a novel approach to cancer therapy.

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Khuda-Bukhsh, Anisur Rahman, and Sourav Sidkar. "Hypermethylation involved in DNA profiles of lung cancer specific tumour suppressor genes and epigenetic modification caused by an ultra-highly diluted homeopathic drug, Condurango 30C, in vitro and in vivo." International Journal of High Dilution Research - ISSN 1982-6206 13, no. 47 (November 30, 2021): 99. http://dx.doi.org/10.51910/ijhdr.v13i47.721.

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Background and objectives: DNA hyper-methylation is an important aspect involved in carcinogenesis and cancer progression, which affects mainly CpG islands of DNA and causes inactivation of tumour suppressor genes. Therefore DNA hypermethylation status of the genomic DNA in both the transformed cancerous cell lines and in carcinogen-induced lung cancer was ascertained by analysis of expressions of certain major lung cancer specific tumour suppressor genes. The other objective was to examine if ultra highly diluted homeopathic drug, Condurango 30C, had ability to modulate DNA methylation. Methods: DNA methylation activity, if any, has been ascertained in H460-NSCLC cells in vitro and in BaP-induced lung cancer of rats in vivo, in respect of tumour suppressor genes like p15, p16, p18 and p53 by using PCR-SSCP analyses. The ability of modulation of DNA methylation, if any, by Condurango 30C was also verified against placebo control in a blinded manner. Results: Condurango 30C-treated DNA showed significant decrease in band-intensity of p15 and p53 genes especially in methylated condition, in vitro, at the IC50 dose (2.43Âµl/100Âµl). SSCP analysis of p15 and p53 genes in Condurango 30C-treated DNA also supported ability of Condurango 30C to modulate methylation state, in vitro. Inhibition of p15 hypermethylation was observed after post cancer treatment of rat with Condurango 30C. SSCP results gave a better indication of differences in band-position and single strand separation of p15 and p53 in Condurango 30C treated samples. Conclusion: Condurango 30C could trigger epigenetic modification in lung cancer via modulation of DNA hypermethylation but placebos could not.

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Kong, Na, Wei Tao, Xiang Ling, Junqing Wang, Yuling Xiao, Sanjun Shi, Xiaoyuan Ji, et al. "Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition." Science Translational Medicine 11, no. 523 (December 18, 2019): eaaw1565. http://dx.doi.org/10.1126/scitranslmed.aaw1565.

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Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non–small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

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Laín, S. "Protecting p53 from degradation." Biochemical Society Transactions 31, no. 2 (April 1, 2003): 482–85. http://dx.doi.org/10.1042/bst0310482.

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Inactivation of the p53 function is a common event in cancer. Approx. 50% of human tumours express mutant p53 and there is evidence that in others, including many childhood tumours, p53 function is impaired in other ways. These defects on p53 function may be due to the alteration of cellular factors that modulate p53 or to the expression of viral oncoproteins. Radiotherapy and many of the chemotherapeutic drugs currently used in cancer treatment are potent activators of p53. However, most of these therapies have a serious drawback; that is, the long-term consequences of their DNA-damaging effects. Understanding the mechanisms regulating p53 stability is crucial for the development of new strategies to activate p53 non-genotoxically. Here we describe the effect of a potent activator of the p53 response, the nuclear export inhibitor leptomycin B, on Mdm2 degradation and we provide evidence for the oligomerization of the p14ARF tumour suppressor and Mdm2 inhibitor in response to oxidative stress.

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Försti, Asta, Qianren Jin, Lena Sundqvist, Magnus Söderberg, and Kari Hemminki. "Use of Monozygotic Twins in Search for Breast Cancer Susceptibility Loci." Twin Research 4, no. 4 (August 1, 2001): 251–59. http://dx.doi.org/10.1375/twin.4.4.251.

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AbstractWe have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel, including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.

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Lees, Andrea, Tamas Sessler, and Simon McDade. "Dying to Survive—The p53 Paradox." Cancers 13, no. 13 (June 29, 2021): 3257. http://dx.doi.org/10.3390/cancers13133257.

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The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.

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Meek, David W. "Regulation of the p53 response and its relationship to cancer1." Biochemical Journal 469, no. 3 (July 23, 2015): 325–46. http://dx.doi.org/10.1042/bj20150517.

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p53 has been studied intensively as a major tumour suppressor that detects oncogenic events in cancer cells and eliminates them through senescence (a permanent non-proliferative state) or apoptosis. Consistent with this role, p53 activity is compromised in a high proportion of all cancer types, either through mutation of the TP53 gene (encoding p53) or changes in the status of p53 modulators. p53 has additional roles, which may overlap with its tumour-suppressive capacity, in processes including the DNA damage response, metabolism, aging, stem cell differentiation and fertility. Moreover, many mutant p53 proteins, termed ‘gain-of-function’ (GOF), acquire new activities that help drive cancer aggression. p53 is regulated mainly through protein turnover and operates within a negative-feedback loop with its transcriptional target, MDM2 (murine double minute 2), an E3 ubiquitin ligase which mediates the ubiquitylation and proteasomal degradation of p53. Induction of p53 is achieved largely through uncoupling the p53–MDM2 interaction, leading to elevated p53 levels. Various stress stimuli acting on p53 (such as hyperproliferation and DNA damage) use different, but overlapping, mechanisms to achieve this. Additionally, p53 activity is regulated through critical context-specific or fine-tuning events, mediated primarily through post-translational mechanisms, particularly multi-site phosphorylation and acetylation. In the present review, I broadly examine these events, highlighting their regulatory contributions, their ability to integrate signals from cellular events towards providing most appropriate response to stress conditions and their importance for tumour suppression. These are fascinating aspects of molecular oncology that hold the key to understanding the molecular pathology of cancer and the routes by which it may be tackled therapeutically.

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O'Leary, Kathleen A., Susan M. Mendrysa, Abram Vaccaro, and Mary Ellen Perry. "Mdm2 Regulates p53 Independently of p19ARF in Homeostatic Tissues." Molecular and Cellular Biology 24, no. 1 (January 1, 2004): 186–91. http://dx.doi.org/10.1128/mcb.24.1.186-191.2004.

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ABSTRACT Tumor suppressor proteins must be exquisitely regulated since they can induce cell death while preventing cancer. For example, the p19ARF tumor suppressor (p14ARF in humans) appears to stimulate the apoptotic function of the p53 tumor suppressor to prevent lymphomagenesis and carcinogenesis induced by oncogene overexpression. Here we present a genetic approach to defining the role of p19ARF in regulating the apoptotic function of p53 in highly proliferating, homeostatic tissues. In contrast to our expectation, p19ARF did not activate the apoptotic function of p53 in lymphocytes or epithelial cells. These results demonstrate that the mechanisms that control p53 function during homeostasis differ from those that are critical for tumor suppression. Moreover, the Mdm2/p53/p19ARF pathway appears to exist only under very restricted conditions.

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Donehower, Lawrence A., and Allan Bradley. "The tumore suppressor p53." Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1155, no. 2 (August 1993): 181–205. http://dx.doi.org/10.1016/0304-419x(93)90004-v.

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Miyajima, Chiharu, Yuki Kawarada, Yasumichi Inoue, Chiaki Suzuki, Kana Mitamura, Daisuke Morishita, Nobumichi Ohoka, Takeshi Imamura, and Hidetoshi Hayashi. "Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence." Cells 9, no. 1 (January 9, 2020): 171. http://dx.doi.org/10.3390/cells9010171.

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Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.

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Cao, Zhijie, Ning Kon, Yajing Liu, Wenbin Xu, Jia Wen, Han Yao, Mi Zhang, et al. "An unexpected role for p53 in regulating cancer cell–intrinsic PD-1 by acetylation." Science Advances 7, no. 14 (March 2021): eabf4148. http://dx.doi.org/10.1126/sciadv.abf4148.

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Cancer cell–intrinsic programmed cell death protein-1 (PD-1) has emerged as a tumor regulator in an immunity-independent manner, but its precise role in modulating tumor behaviors is complex, and how PD-1 is regulated in cancer cells is largely unknown. Here, we identified PD-1 as a direct target of tumor suppressor p53. Notably, p53 acetylation at K120/164 played a critical role in p53-mediated PD-1 transcription. Acetylated p53 preferentially recruited acetyltransferase cofactors onto PD-1 promoter, selectively facilitating PD-1 transcription by enhancing local chromatin acetylation. Reexpression of PD-1 in cancer cells inhibited tumor growth, whereas depletion of cancer cell–intrinsic PD-1 compromised p53-dependent tumor suppression. Moreover, histone deacetylase inhibitor (HDACi) activated PD-1 in an acetylated p53–dependent manner, supporting a synergistic effect by HDACi and p53 on tumor suppression via stimulating cancer cell–intrinsic PD-1. Our study reveals a mechanism for activating cancer cell–intrinsic PD-1 and indicates that p53-mediated PD-1 activation is critically involved in tumor suppression in an immunity-independent manner.

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Coronel, Luis, Konstantin Riege, Katjana Schwab, Silke Förste, David Häckes, Lena Semerau, Stephan H. Bernhart, Reiner Siebert, Steve Hoffmann, and Martin Fischer. "Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress." Nucleic Acids Research 49, no. 13 (July 1, 2021): 7437–56. http://dx.doi.org/10.1093/nar/gkab575.

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Abstract Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7’s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.

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Hainaut, Pierre. "The tumor suppressor protein p53." Current Opinion in Oncology 7, no. 1 (January 1995): 76–82. http://dx.doi.org/10.1097/00001622-199501000-00012.

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Hainaut, Pierre. "The tumor suppressor protein p53." Current Opinion in Oncology 7, no. 1 (January 1995): 76–82. http://dx.doi.org/10.1097/00001622-199507010-00012.

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Journal articles on the topic 'P53; tumour suppressor; cancer'

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