Academic literature on the topic 'Mutant p53 gain of function'
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Journal articles on the topic "Mutant p53 gain of function"
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Stein, Yan, Varda Rotter, and Ronit Aloni-Grinstein. "Gain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis." International Journal of Molecular Sciences 20, no. 24 (December 8, 2019): 6197. http://dx.doi.org/10.3390/ijms20246197.
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The p53 protein is mutated in about 50% of human cancers. Aside from losing the tumor-suppressive functions of the wild-type form, mutant p53 proteins often acquire inherent, novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function (GOF). A growing body of evidence suggests that these pro-oncogenic functions of mutant p53 proteins are mediated by affecting the transcription of various genes, as well as by protein–protein interactions with transcription factors and other effectors. In the current review, we discuss the various GOF effects of mutant p53, and how it may serve as a central node in a network of genes and proteins, which, altogether, promote the tumorigenic process. Finally, we discuss mechanisms by which “Mother Nature” tries to abrogate the pro-oncogenic functions of mutant p53. Thus, we suggest that targeting mutant p53, via its reactivation to the wild-type form, may serve as a promising therapeutic strategy for many cancers that harbor mutant p53. Not only will this strategy abrogate mutant p53 GOF, but it will also restore WT p53 tumor-suppressive functions.
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Hall, Callum, and Patricia A. J. Muller. "The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer." International Journal of Molecular Sciences 20, no. 24 (December 7, 2019): 6188. http://dx.doi.org/10.3390/ijms20246188.
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The p53 family of proteins has grown substantially over the last 40 years. It started with p53, then p63, p73, isoforms and mutants of these proteins. The function of p53 as a tumour suppressor has been thoroughly investigated, but the functions of all isoforms and mutants and the interplay between them are still poorly understood. Mutant p53 proteins lose p53 function, display dominant-negative (DN) activity and display gain-of-function (GOF) to varying degrees. GOF was originally attributed to mutant p53′s inhibitory function over the p53 family members p63 and p73. It has become apparent that this is not the only way in which mutant p53 operates as a large number of transcription factors that are not related to p53 are activated on mutant p53 binding. This raises the question to what extent mutant p53 binding to p63 and p73 plays a role in mutant p53 GOF. In this review, we discuss the literature around the interaction between mutant p53 and family members, including other binding partners, the functional consequences and potential therapeutics.
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Chen, Sisi, Hao Yu, Michihiro Kobayashi, Rui Gao, H. Scott Boswell, and Yan Liu. "Gain-of-Function Mutant p53 Enhances Hematopoietic Stem Cell Self-Renewal." Blood 124, no. 21 (December 6, 2014): 260. http://dx.doi.org/10.1182/blood.v124.21.260.260.
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Abstract The tumor suppressor p53 is a critical regulator of hematopoietic stem cell (HSC) behavior and we demonstrated that p53 maintains HSC quiescence and regulates HSC response to irradiation (Liu et al., Cell Stem Cell, 2009).While TP53 mutations are less common in acute myeloid leukemia (5 to 8%) than in solid tumors (50%), they are associated with poor prognosis and abnormal cytogenetics, especially abnormalities in chromosomes 5 and 7. These mutations may abolish some but not necessarily all of the functions of p53 in regulating stem cell behavior. Therefore, this aspect of p53 function needs further investigation. To define the role of mutant p53 in the pathogenesis of AML, we introduced 9 hot-spot p53 mutants identified in AML patients, including p53R248W, p53R273H and p53Y220C, into wild type hematopoietic cells using retrovirus-mediated transduction and investigated the role of these p53 mutants in regulating HSC self-renewal. We found that hematopoietic cells expressing p53R248W, p53Y220C or p53R273H show enhanced repopulating potential 16 weeks following transplantation. As codon 248 of the p53 protein is most frequently mutated in AML, we decided to investigate the role of p53R248W mutant in HSCs by using the humanized knock-in mice of p53R248W. In p53 knockout mice, there is a dramatic increase of HSCs (CD48-CD150+Lin-Sca1+c-Kit+ cells); however,we found thatboth wild type andp53R248W mice have similar number of HSCs. While wild type p53 maintains HSC quiescence, expression of p53R248W in HSCs (CD48-CD150+LSKs) does not affect their quiescent state. Asp53R248W does not appear to affect HSC frequency and quiescence, it is not a loss-of-function mutant. We also used bone marrow cells isolated from both wild type and p53R248W mice to perform the serial replating assays and found that expressing p53R248W from the endogenous Trp53 promoter enhances the replating potential of hematopoietic cells. Moreover, we performed serial bone marrow repopulation (BMT) assays and found that the repopulating ability of p53R248W cells was significantly higher than that of the wild type cells in both primary and secondary BMT assays, demonstrating that the p53R248W mutant enhances HSC self-renewal in vivo. Furthermore, we observed that HSCs expressing p53R248W are resistant to genotoxic stress induced by irradiation and the p53R248W mice show extended survival following sub-lethal dose of total body irradiation. Ample data indicate that mutant p53 proteins not only lose their tumor suppressive functions, but also gain new abilities that promote tumorigenesis. To understand how mutant p53 enhances HSC self-renewal, we performed gene expression profiling assays by using HSCs isolated from wild type and p53R248W mice. We also utilized Ingenuity Pathway analysis software to group putative mutant p53 target genes into different pathways. While we did not observe change in the expression of p53 target genes in p53R248W HSCs, several pathways that are important for leukemogenesis, including epigenetic and DNA damage repair pathways, are altered in HSCs expressing p53R248W, demonstrating that p53R248W is a gain-of-function mutant. Given that TP53 mutations are correlated with poor prognosis, pharmacological inhibition of mutant p53 may be a promising therapeutic strategy for AML patients with TP53 mutations. Small molecule PRIMA-1 has been shown to restore wild-type conformation to some mutant p53 proteins and induce apoptosis in human tumor cells. We found that hematopoietic cells expressing mutant p53 are sensitive to PRIMA-1 treatment and undergo p53-dependent apoptosis. Furthermore, we observed that PRIMA-1 inhibits the growth of primary human AML cells with TP53 mutation in a dosage-dependent manner. Taken together, we demonstrated that gain-of-function mutant p53 enhances hematopoietic stem cell self-renewal through regulating epigenetic and DNA damage repair pathways. Our data also suggest that pharmacological inhibition of mutant p53 may sensitize the drug-resistant leukemia stem cells (LSCs) to chemotherapy and improves leukemia treatment. Disclosures No relevant conflicts of interest to declare.
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Chiang, Yen-Ting, Yi-Chung Chien, Yu-Heng Lin, Hui-Hsuan Wu, Dung-Fang Lee, and Yung-Luen Yu. "The Function of the Mutant p53-R175H in Cancer." Cancers 13, no. 16 (August 13, 2021): 4088. http://dx.doi.org/10.3390/cancers13164088.
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Wild-type p53 is known as “the guardian of the genome” because of its function of inducing DNA repair, cell-cycle arrest, and apoptosis, preventing the accumulation of gene mutations. TP53 is highly mutated in cancer cells and most TP53 hotspot mutations are missense mutations. Mutant p53 proteins, encoded by these hotspot mutations, lose canonical wild-type p53 functions and gain functions that promote cancer development, including promoting cancer cell proliferation, migration, invasion, initiation, metabolic reprogramming, angiogenesis, and conferring drug resistance to cancer cells. Among these hotspot mutations, p53-R175H has the highest occurrence. Although losing the transactivating function of the wild-type p53 and prone to aggregation, p53-R175H gains oncogenic functions by interacting with many proteins. In this review, we summarize the gain of functions of p53-R175H in different cancer types, the interacting proteins of p53-R175H, and the downstream signaling pathways affected by p53-R175H to depict a comprehensive role of p53-R175H in cancer development. We also summarize treatments that target p53-R175H, including reactivating p53-R175H with small molecules that can bind to p53-R175H and alter it into a wild-type-like structure, promoting the degradation of p53-R175H by targeting heat-shock proteins that maintain the stability of p53-R175H, and developing immunotherapies that target the p53-R175H–HLA complex presented by tumor cells.
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Oren, M., and V. Rotter. "Mutant p53 Gain-of-Function in Cancer." Cold Spring Harbor Perspectives in Biology 2, no. 2 (December 16, 2009): a001107. http://dx.doi.org/10.1101/cshperspect.a001107.
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Aschauer, Lydia, and Patricia A. J. Muller. "Novel targets and interaction partners of mutant p53 Gain-Of-Function." Biochemical Society Transactions 44, no. 2 (April 11, 2016): 460–66. http://dx.doi.org/10.1042/bst20150261.
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In many human cancers p53 expression is lost or a mutant p53 protein is expressed. Over the past 15 years it has become apparent that a large number of these mutant p53 proteins have lost wild type function, but more importantly have gained functions that promote tumorigenesis and drive chemo-resistance, invasion and metastasis. Many researchers have investigated the underlying mechanisms of these Gain-Of-Functions (GOFs) and it has become apparent that many of these functions are the result of mutant p53 hijacking other transcription factors. In this review, we summarize the latest research on p53 GOF and categorize these in light of the hallmarks of cancer as presented by Hannahan and Weinberg.
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Zhang, Yanhong, Wensheng Yan, and Xinbin Chen. "Mutant p53 Disrupts MCF-10A Cell Polarity in Three-dimensional Culture via Epithelial-to-mesenchymal Transitions." Journal of Biological Chemistry 286, no. 18 (March 22, 2011): 16218–28. http://dx.doi.org/10.1074/jbc.m110.214585.
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Mutant p53 is not only deficient in tumor suppression but also acquires additional activity, called gain of function. Mutant p53 gain of function is recapitulated in knock-in mice that carry one null allele and one mutant allele of the p53 gene. These knock-in mice develop aggressive tumors compared with p53-null mice. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for cell survival and resistance to DNA damage. To further define mutant p53 gain of function, we used the MCF-10A three-dimensional model of mammary morphogenesis. MCF-10A cells in three-dimensional culture undergo a series of morphological changes and form polarized and growth-arrested spheroids with hollow lumen, which resembles normal glandular architectures in vivo. Here, we found that endogenous wild-type p53 in MCF-10A cells was not required for acinus formation, but knockdown of endogenous wild-type p53 (p53-KD) led to partial clearance of cells in the lumen due to decreased apoptosis. Consistent with this, p53-KD altered expression patterns of the cell adhesion molecule E-cadherin, the cytoskeletal marker β-catenin, and the extracellular matrix protein laminin V. We also found that ectopic expression of the mutant G245S led to a phenotype similar to p53-KD, whereas a combination of ectopic expression of siRNA-resistant G245S with p53-KD led to a less cleared lumen. In contrast, ectopic expression of mutant R248W, R175H, and R273H disrupted normal acinus architectures with filled lumen and led to formation of irregular and multiacinus structures regardless of p53-KD. In addition, these mutants altered normal expression patterns and/or levels of E-cadherin, β-catenin, laminin V, and tight junction marker ZO-1. Furthermore, epithelial-to-mesenchymal transitions (EMT) markers, Snail, Slug, and Twist, were highly induced by mutant p53 and/or p53-KD. Together, we postulate that EMT represents a mutant p53 gain of function and mutant p53 alters cell polarity via EMT.
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Zhang, Cen, Juan Liu, Dandan Xu, Tianliang Zhang, Wenwei Hu, and Zhaohui Feng. "Gain-of-function mutant p53 in cancer progression and therapy." Journal of Molecular Cell Biology 12, no. 9 (July 28, 2020): 674–87. http://dx.doi.org/10.1093/jmcb/mjaa040.
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Abstract p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in >50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.
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Cai, Bi-He, Zhi-Yu Bai, Ching-Feng Lien, Si-Jie Yu, Rui-Yu Lu, Ming-Han Wu, Wei-Chen Wu, Chia-Chi Chen, and Yi-Chiang Hsu. "NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner." Biomolecules 12, no. 3 (March 12, 2022): 438. http://dx.doi.org/10.3390/biom12030438.
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The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.
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Zhang, Ying, Feng Yuan, Cassandra Grello, Brian Reon, Myron Gibert, Collin Dube, Anindya Dutta, Eric Holland, and Roger Abounader. "CSIG-07. GAIN-OF-FUNCTION MUTANT P53 REGULATES LONG-NONCODING RNAS IN GLIOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii39—vii40. http://dx.doi.org/10.1093/neuonc/noac209.156.
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Abstract P53 is frequently mutated in most human cancers, including glioblastoma (GBM). Many p53 mutants acquire gain-of-function oncogenic effects through only partially understood mechanisms. To investigate the role of gain-of-function mutant p53 (MUT-p53) in GBM, we performed ChIP-seq of wildtype p53 (WT-p53) and MUT-p53 GBM cell lines. Among 2834 unique peaks reads in MUT-p53 cells, we found 242 long non-coding RNAs (lncRNAs) with up to 145 fold enrichment relative to WT-p53. LncRNAs regulate many molecular and cellular functions, including gene expression, cell proliferation, death, cancer stem cell renewal and differentiation. We selected lncRNAs SOX21-AS1 and LINC00643 with highly enriched binding by MUT-p53 and investigated their expressions and functions in the p53 pathway. We performed ChIP confirmation of MUT-p53 binding to the promoters of these lncRNAs. We found that these lncRNAs are deregulated in GBM and correlated with GBM patient survival in the TCGA database. To investigate the functions of these LncRNAs, we knocked down their expressions by siRNA, and found significant cell death induced by si-SOX21-AS1, but not by si-LINC00643. Overexpression of LINC00643 in GBM cells led to inhibition of GBM cell proliferation, migration, invasion and in vivo xenograft growth. LINC00643 mediated the effects of MUT-p53. Co-expression of human LINC00643 and its mouse homologous in a RCAS transgenic mouse model of GBM reduced tumor growth and improved animal survival. To elucidate the mechanisms of action of the lncRNA, we performed Chromatin Isolation by RNA purification high-throughput sequencing (CHIRP-seq) to identify its binding targets. We found that LINC00643 binds to HIF1a 5’ promoter/enhancer region. Overexpression of LINC00643 in GBM cells at hypoxia growth condition reduced HIF1a mRNA and protein expression. Our study shows for the first time that gain-of-function mutant p53 regulates a subset of lncRNAs and that the lncRNAs mediate the oncogenic effects of the MUT-p53 in GBM.
Dissertations / Theses on the topic "Mutant p53 gain of function"
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Vaughan, Catherine. "Investigation of Gain-of-Function Induced by Mutant p53." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3965.
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p53 is mutated in 50% of all human cancers, and up to 70% of lung cancer. Mutant p53 is usually expressed at elevated levels in cancer cells and has been correlated with a poor prognosis. Cancer cells that express mutant p53 show an increase in oncogenic phenotypes including an increase in growth rate, resistance to chemotherapeutic drugs, and an increase in motility and tumorigenicity to name a few. We have identified several genes involved in cell growth and survival that are upregulated by expression of common p53 mutants: NFκB2, Axl, and epidermal growth factor receptor (EGFR). The aim of this study was to determine the role NFκB2, Axl, and EGFR play in mutant p53’s gain of function (GOF) phenotype and to determine a mechanism for upregulation of mutant p53 target gene upregulation.
Inhibition of mutant p53 in various cancer cell lines using RNAi in the form of transient siRNA transfection or stable shRNA cell line generation caused a decrease in the gain of function ability of those cells in the form of reduced chemoresistance, reduced cell growth and motility, and a reduction in tumor formation. Additionally, inhibition of NFκB2, Axl, and EGFR also showed similar effects. Promoter deletion analysis of the NFκB2 promoter did not show a specific mutant p53 response element needed for mutant p53 mediated transactivation. Similarly, deletion of the p53/p63 binding site on the Axl promoter did not inhibit mutant p53 transactivation. Sequence analysis of the NFκB2, Axl, and EGFR promoters revealed several transcription factor binding sites located throughout the promoters. ChIP analysis of mutant p53 and the promoter-specific transcription factor binding revealed that in the presence of mutant p53, individual transcription factor binding is increased to the NFκB2, Axl, and EGFR promoters as well as an increase in acetylated histone binding. This data suggests that mutant p53 promotes an increase in transcription by inducing acetylation of histones via recruitment of transcription factors to the promoters of mutant p53 target genes.
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Turrell, Frances Kathryn. "Gain-of-function and dominant-negative effects of distinct p53 mutations in lung tumours." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/271848.
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Lung cancer is the most common cause of cancer-related mortality worldwide with current treatments providing limited therapeutic benefit in most cases. TP53 (Trp53, p53) mutations occur in approximately 50% of lung adenocarcinoma cases and are associated with poor prognosis and so novel therapies that target these p53 mutant lung tumours are urgently needed. Despite the high frequency of p53 mutations in lung tumours, the impact these mutations have on response to therapy remains unclear in this cancer type. The aim of my project is to characterise the gain-of-function and dominant-negative effects of p53 mutations in lung tumours and to identify ways of therapeutically targeting these p53 mutant tumours based on dependencies and susceptibilities that our analysis uncovers. To characterise the gain-of-function and dominant-negative effects of p53 mutations I compared p53 mutant murine lung tumour cells that endogenously express either a contact (R270H, equivalent to R273H in humans) or conformational (R172H, equivalent to R175H in humans) p53 mutant protein and p53 null lung tumour cell lines; both in the presence and absence of wild-type p53. Interestingly, transcriptional and functional analysis uncovered metabolic gain-of-functions that are specific to the type of p53 mutation. Upregulation of mevalonate pathway expression was observed only in R270H lung tumours and consequently R172H and R270H lung tumours displayed distinct sensitivities to simvastatin, a mevalonate pathway inhibitor widely used in the clinic. Furthermore, the transcriptional signature underlying this sensitivity to simvastatin was also present in human lung tumours with contact p53 mutations, indicating that these findings may be clinically relevant. On the other hand, our analysis of the potential dominant-negative effects of the p53 mutants on wild-type p53 demonstrated that wild-type p53 was able to induce typical p53 target genes to a similar level in p53 null and mutant cells. Furthermore, wild-type p53 restoration resulted in comparable tumour suppressive responses in p53 mutant and null tumours and thus, p53-restoration therapy will likely be of benefit to patients with p53 mutations in lung cancer. Hence, I have demonstrated that lung tumours harbouring contact and conformational p53 mutations display common and distinct therapeutic susceptibilities.
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Heath, Nikki. "An investigation into the role of microvesicles in mutant p53 invasive gain-of-function." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6895/.
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p53 is a transcription factor with tumour suppressive attributes which is known to be mutated in over half of human cancers. As well as compromising the ability of p53 to function as a transcription factor, mutations in p53 often result in a gain-of-function phenotype which is characterised by increased ability of cancer cells to migrate and invade. This is mediated by the ability of mutant p53 to increase recycling of α5β1 integrin and receptor tyrosine kinases (RTK) from endosomes to the plasma membrane; a process which is dependent on the Rab11 effector, Rab Coupling Protein (RCP) and the phosphatidic acid generating enzyme, diacylglycerol kinase-α (DGKα). Despite accumulating evidence linking RCP/DGKα-dependent receptor recycling to invasive migration, the mechanisms by which mutant p53 controls endosomal trafficking were still unclear when the current study was instigated. Initial experiments indicated that the mutant p53 gain-of-function phenotype was not cell autonomous, and could be passed to p53 null cells by incubating them with conditioned medium from mutant p53 (R273H)-expressing cells. Furthermore, fractionation approaches indicated that the mutant p53 phenotype was transmitted between cells by a microvesicle vector. Upon treatment with microvesicles collected from mutant p53 expressing cells, p53 null cells displayed increased α5β1 integrin and RTK recycling and the consequent invasive/migratory behaviour that was dependent on these RCP and DGKα-regulated trafficking events. Despite a requirement for RCP in the response of p53 null cells to microvesicles, this Rab11 effector was not required for the production of pro-invasive microvesicles. Rather, mutant p53-expressing cells relied on Rab35 (but not Rab27a or Rab27b) for the production and/or release of microvesicles that were capable of transferring mutant p53’s gain-of-function phenotype. An in-depth RNA sequencing analysis indicated that microvesicles from mutant p53 cells influenced the endocytic trafficking and migratory characteristics of p53 null cells without detectably altering mRNA expression in these recipient cells. This indicated the possibility that microvesicles from mutant p53-expressing cells may act directly on the endomembrane system of recipient cells. Immunoprecipitation experiments indicated that there was a physical interaction between Rab35 and podocalyxin (PODXL), a highly-charged sialomucin which is known to directly influence membrane organisation. Additionally, PODXL was detectable in microvesicular preparations by mass spectrometry. Microvesicles purified from mutant p53-expressing cells in which PODXL had been knocked down using siRNA, had significantly reduced capacity to promote integrin/RTK recycling and mutant p53-like migratory behaviour in p53 null cells, indicating that PODXL, as well as Rab35, is a key factor responsible for transmitting mutant p53’s gain-of-function phenotype between cells. In addition to being incapable of influencing the migration of other cells, Rab35 knockdown cells themselves migrated with the characteristics of p53 null cells. Interestingly, microvesicles from mutant p53-expressing cells restored mutant p53-like migratory behaviour in these Rab35 knockdown cells. These data indicate that Rab35 and PODXL-dependent production of phenotype altering microvesicles not only influences the migration of neighbouring cells in a paracrine fashion, but may constitute an autocrine link between mutant p53 and integrin trafficking in the mutant p53 cells themselves. Finally, I have found that p53 null cells may be educated by microvesicles from mutant p53-expressing cells to themselves release cell migration-altering microvesicles, providing further evidence supporting the existence of microvesicle-based autocrine/paracrine mechanisms that may act to propagate mutant p53’s invasive gain-of-function within both homogeneous and heterogeneous populations of tumour cells.
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Scian, Mariano J. "MODULATION OF GENE EXPRESSION BY TUMOR-DERIVED MUTANT p53. ROLE OF TRANSACTIVATION IN GAIN-OF-FUNCTION." VCU Scholars Compass, 2005. https://scholarscompass.vcu.edu/etd/5518.
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It was hypothesized that the C-terminal sequences for mutant p53 would be required for oligomerization. and oligomerization may be critical for gain-of-function. An N-terminal deletion mutant of p53 that deletes amino acids 1-293 was used as a tool to perform hetero-oligomerization studies. This mutant retains the entire oligomerization domain but dispenses off the transactivation domain and a large portion of the sequence- specific DNA-binding domain. Co-transfection experiments show that p53 del. 1-293 forms hetero-oligomeric complexes with p53-D281G. Also. co-expression of p53 del. 1- 293 with p53-D281G inhibited p53-D28lG-mediated transactivation of the EGFR and MDRl promoters suggesting that hetero-oligomerization inactivates transcriptional functions of mutant p53. The interaction of p53 deli 1-293 and p53-D281G reduced transactivation potential of p53-D281G in stably transfected 10(3) murine cells. Therefore, the data presented supports the idea that proper oligomeric forms of mutant p53 are required for its transactivation function. Expression of mutant p53-D2810 also resulted in increased growth rate (H1299 cells), decreased chemosensitivity (H1299 and 21PT cells) and increased plating efficiency (Saos-2 cells). Expression of a transactivation deficient mutant p53 did not induce gain-of-function properties (increased growth rate and decreased chemosensitivity). Unlike the other gain-of-function properties tested, soft agar plating efficiency in Saos-2 cells was not significantly affected by the expression of a transactivation deficient mutant p53, suggesting that transactivation may not be the only factor affecting this gain-of-function property In order to identify the genes responsible for the observed phenotypes, global gene expression analyses were carried out using p53-null H1299 cell stably transfected to express mutant p53 (-Rl75H, -R273H and -D281G). A thorough and stringent analysis revealed 150 genes up-regulated by the expression of mutant p53. Up-regulation of a number of these genes was confirmed by QPCR and transient transcriptional promoter analyses; expression of the transactivation deficient mutant p53-D2810 (L22Q/W23S) did not result in up-regulation of the tested genes further supporting the idea that transactivation of genes is directly related to gain-of-function phenotypes. Using the ASNS gene as a model, this transactivation by mutant p53 was concentration dependent and that the increased transcription did indeed result in increased protein levels.
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Wülfing, Verena [Verfasser], and Jochen [Akademischer Betreuer] Dahm-Daphi. "Stimulation of Homologous Recombination by P53 gain-of-function mutant M237I / Verena Wülfing. Betreuer: Jochen Dahm-Daphi." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2012. http://d-nb.info/1027574041/34.
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Napoli, Marco. "A Pin1/mutant p53 axis promotes aggressiveness in breast cancer." Doctoral thesis, Università degli studi di Trieste, 2011. http://hdl.handle.net/10077/4602.
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2009/2010Mutations in the TP53 gene are among the most frequent genetic alterations in human cancers. As a consequence of these mutations p53 loses its tumour suppressor functions and may acquire novel oncogenic activities (gain of function) sustaining tumour formation and progression. Many in vivo studies highlighted that mutant p53 gain of function is associated with elevated protein levels, supporting the notion that in tumour cells altered signalling could stabilize and activate mutant p53, with mechanisms similar to those required to stimulate wild-type p53. The aim of my PhD work was to investigate the mechanisms underlying mutant p53 gain of function, focusing on factors that might link cancer-related signalling with mutant p53 activity. An intriguing candidate for this role is the phosphorylationdependent prolyl isomerase Pin1, that transduces phosphorylation signalling into conformational changes affecting the functions of its substrates, as ours and other laboratories have reported for wild-type p53. Despite Pin1 supports wild-type p53 functions, Pin1 is frequently overexpressed in human tumours and has been shown to promote both Her2/Neu/Ras and Notch1 dependent transformation. So we reasoned that the physiological role of Pin1 as a component of checkpoint mechanisms might be subverted during tumourigenesis, thereby turning it into an essential partner of mutant p53 and a critical amplifier of its oncogenic functions. Indeed, we now demonstrate that Pin1 enhances tumourigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent cell transformation. In human breast cancer cells, Pin1 promotes both mutant p53 dependent inhibition of the anti-metastatic factor p63 and the induction of a mutant p53 transcriptional program to increase tumor aggressiveness. Accordingly, we have identified a transcriptional signature (the Pin1/mutant p53 signature) that is associated with poor prognosis in breast cancer and, in a cohort of patients, Pin1 over-expression influences the prognostic value of p53 mutation. Considering that TP53 mutation is more frequent in tumors with higher risk of recurrence such as triple-negative cases and that some of the Pin1/mutant p53 signature genes are over-expressed in triple negative breast cancers, our findings carry therapeutic implications for this kind of cancers and possibly also for other tumours bearing mutant p53 and high levels of Pin1.
XXII Ciclo
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Masood, Rubana. "The Effects of Gain of Function Mutant p53 and p63 on EPS8 and CXCL5 Expression in Head and Neck Squamous Cell Carcinoma." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/530.
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Head and neck squamous cell carcinoma (HNSCC) is one of the ten most common cancers worldwide, with a survival rate of less than 50%. A class of mutant p53, known as gain of function (GOF) mutant p53, has been found to be expressed in tumors in these patients. GOF mutant p53 not only loses the wild type tumor suppressor functions, but also gains aberrant functions that have been linked to tumorigenesis. In this current study, we utilized a model system consisting of cells derived from HNSCC tumors in order to investigate our hypothesis that GOF mutant p53 enhances, and p63 inhibits, EPS8 and CXCL5 expression and promoter activity. We found decreased EPS8 expression, CXCL5 expression, and cellular migration associated with the loss of GOF mutant p53. This indicates an enhancing role of GOF mutant p53 in cellular migration and expression of these target genes. The loss of GOF mutant p53 was also associated with decreased EPS8 and CXCL5 promoter activity, indicating upregulation of these target gene promoters by GOF mutant p53. We found increased EPS8 expression,CXCL5 expression, and cellular migration with the loss of p63 in cell expressing high levels of p63. This indicates an ixinhibitory role of p63 on the expression of these target genes and cellular migration. Loss of p63 was also associated with increased EPS8 and CXCL5 promoter activity, indicating p63 may be downregulating these target gene promoters. Based on our knowledge of EPS8 and CXCL5 in tumorigenesis, our findings suggest that GOF mutant p53 and p63 play opposing rolesin HNSCC tumorigenesis. Additional studies are needed to further elucidate the mechanism by which GOF mutant p53 and p63 regulate EPS8 and CXCL5 expression and promoter activity.
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Gadepalli, Venkat Sundar. "ISOLATION AND CHARACTERIZATION OF MULTIPOTENT LUNG STEM CELLS FROM p53 MUTANT MICE MODELS." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3644.
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Recent advances in understanding lung biology have shown evidence for the existence of resident lung stem cells. Independent studies in identifying and characterizing these somatic lung stem cells have shown the potential role of these cells in lung repair and regeneration. Understanding the functional characteristics of these tissue resident stem/progenitor cells has gained much importance with increasing evidence of cancer stem cells, cells in a tumor tissue with stem cell characteristics. Lung cancer is most commonly characterized by loss of p53 function which results in uncontrolled cell divisions. Incidence of p53 point mutations is highest in lung cancer, with a high percentage of missense mutations as a result of tobacco smoking. Certain point mutations in p53 gene results in its oncogenic gain of functions (GOF), with enhanced tumorigenic characteristics beyond the loss of p53 function. However, there are no available data on characterization of lung stem cells carrying GOF mutations and correlating them with those of normal stem cells, in this study, for the first time we show that percentage of Sca-1 expressing subpopulation is significantly higher in the lungs of mice carrying p53 GOF mutations than those in lungs isolated from p53+/+ wild type mice. Further, we successfully established lung cells differentially expressing two cell surface markers, Sca-1 and PDGFR-α, with results demonstrating existence of different subpopulations of cells in the lung. Results from our project demonstrate the importance of p53 GOF mutations as correlated with specific lung cell subpopulations.
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Chollat-Namy, Marie. "Effet de l’inactivation du gène suppresseur de tumeur p53 et de sa réactivation pharmacologique sur la réponse cytotoxique anti-tumorale The Pharmalogical Reactivation of p53 Function Improves Breast Tumor Cell Lysis by Granzyme B and NK Cells Through Induction of Autophagy Mutant P53 Gain of Function Stimulates PD-L1 Expression." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL032.
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Le système immunitaire joue un rôle important dans le contrôle et l'éradication du cancer. Des acteurs majeurs de la réponse immune antitumorale sont les cellules tueuses naturelles (ou cellules NK) et les lymphocytes T cytotoxiques (ou CTL), capable de reconnaitre et détruire des cellules tumorales par l’exocytose de perforine et de granzymes contenus dans leur granule cytotoxique. Il a été montré au sein du laboratoire l’implication de la protéine suppresseur de tumeur p53 dans cette voie apoptotique. Or, plus de 50% des tumeurs humaines présentent des mutations inactivatrices de p53 ce qui favorise le développement tumoral. De ce fait, l’inactivation fréquente de p53 dans les tumeurs humaines pourrait leur permettre d’échapper à la destruction par les CTL et les cellules NK.Dans ce contexte, mes travaux de thèse ont montré que la réactivation pharmacologique de la fonction de p53 sauvage dans des cellules tumorales exprimant une p53 mutée augmente leur susceptibilité à la lyse induite par les cellules NK grâce à l’induction d’un processus d’autophagie. De plus, j’ai cherché à déterminer le lien entre les mutations de p53 et l’expression à la surface des cellules tumorales de PD-L1 qui empêche l’activation optimale des cellules cytotoxiques et conduit à leur épuisement. Mes travaux actuels suggèrent que l’expression de p53 mutantes induits une surexpression de PD-L1 à la surface des cellules cancéreuses. Les mécanismes expliquant ce phénomène sont en cours d’étudesImmune system plays an important role in the control and destruction of cancer cells. The major effectors of antitumor immune response are Natural Killer (NK) cells and the cytotoxic T lymphocytes, which recognize et destroy tumor cells by exocytosis of perforin and granzymes contained in cytotoxic granules. It has been previously shown in the laboratory that the tumor suppressor p53 plays an important role in this apoptotic pathway. However more than 50% of human tumors have p53 inactivating mutations which favor tumor development. Consequently, frequent p53 inactivation in human tumor could enable them to escape from destruction by cytotoxic immune cells. In this context, my thesis work has shown that the pharmacological reactivation of wild type p53 function in cancer cells expressing a mutated p53 increased their susceptibility to NK cell-mediated apoptosis cells through the induction of an autophagic process. Moreover, I tried to determine the link between p53 mutations and the expression of the immune checkpoint ligand PD-L1 which prevent efficient activation of cytotoxic cells and promote immune cells exhaustion. My work suggests that the expression of p53 mutants promotes an the expression of PD-L1 at the cancer cell surface. The study of the underlying mechanisms is still in progress
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Choi, Sang H. "Study of p53 Gain of Function Mutations in p53-null Astrocytes." VCU Scholars Compass, 2000. http://scholarscompass.vcu.edu/etd/4420.
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A number of recent studies suggest that expression of mutant p53 with mutations in certain codons show a gain of function and some of the characteristics of an oncoprotein. In order to study gain of function mutation and eliminate the potential of a dominant negative interaction with endogenous wild type p53 protein, p53 knockout mouse astrocytes were used. A retrovirus system was used to introduce mutant p53 genes into these p53-null astrocytes. Immunohistochemical staining and western blot experiments showed the expression of mutant p53 protein in these cells after infection with the mutant p53 retroviruses. Cell growth experiment did not suggest growth advantages for mutant p53 expressing astrocytes over vector control cells. Data from clonogenic survival assays following exposure to etoposide or cisplatin suggested that mutant p53 expressing cells with a point mutation at codon 273 may be resistant to apoptosis induced by etoposide. In contrast, p53 with a point mutation at codon 248 may sensitize cells to the apoptotic effects of etoposide and cisplatin.
Book chapters on the topic "Mutant p53 gain of function"
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Blandino, Giovanni. "Gain-of-Function p53." In Encyclopedia of Cancer, 1–4. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_2302-2.
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Blandino, Giovanni. "Gain-of-Function p53." In Encyclopedia of Cancer, 1828–31. Berlin, Heidelberg: Springer Berlin Heidelberg, 2016. http://dx.doi.org/10.1007/978-3-662-46875-3_2302.
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Blandino, Giovanni. "Gain of Function p53." In Encyclopedia of Cancer, 1486–89. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_2302.
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Das, Priyanka, Rajeev N. Bahuguna, Rohit Joshi, Sneh Lata Singla-Pareek, and Ashwani Pareek. "In search of mutants for gene discovery and functional genomics for multiple stress tolerance in rice." In Mutation breeding, genetic diversity and crop adaptation to climate change, 444–50. Wallingford: CABI, 2021. http://dx.doi.org/10.1079/9781789249095.0045.
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Abstract Mutation breeding is a commanding tool, which has been adapted to generate altered genetic material to study functional genomics, including understanding the molecular basis of stress tolerance. Hitherto, several rice lines have been generated through mutagenesis and the mutated genes responsible for the 'gain of function' in terms of plant architecture, stress tolerance, disease resistance and grain quality have been characterized. Oryza sativa L. cv. IR64 is a high-yielding rice cultivar but sensitive to abiotic stresses such as acute temperatures, salinity and drought. In this study, a population of rice IR64 mutants was generated using gamma irradiation. The population was then subjected to a preliminary phenotypic screening under abiotic stresses such as heat and salinity at the seedling stage. On the basis of root length, shoot length, fresh weight, dry weight and chlorophyll measurements, we identified eight 'gain-of-function' mutant lines and used them for further biochemical and molecular characterization. Phenotyping results demonstrated that the identified mutant plants have gained the potential to thrive under heat and salinity conditions. This information would be of wide scientific interest and helpful for developing novel cultivars able to maintain yield in saline, hot and dry areas.
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Rokudai, Susumu. "High-Throughput RNA Interference Screen Targeting Synthetic-Lethal Gain-of-Function of Oncogenic Mutant TP53 in Triple-Negative Breast Cancer." In Methods in Molecular Biology, 297–303. New York, NY: Springer US, 2020. http://dx.doi.org/10.1007/978-1-0716-0247-8_25.
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"Oncogenomic Approaches in Exploring Gain of Function of Mutant p53." In Advances in Genome Science, edited by Sara Donzelli, Francesca Biagioni, Francesca Fausti, Sabrina Strano, Giulia Fontemaggi, and Giovanni Blandino, 143–60. BENTHAM SCIENCE PUBLISHERS, 2014. http://dx.doi.org/10.2174/9781608058204114030007.
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Acikalin Coskun, Kubra, Merve Tutar, Mervenur Al, Asiye Gok Yurttas, Elif Cansu Abay, Nazlican Yurekli, Bercem Yeman Kiyak, Kezban Ucar Cifci, and Yusuf Tutar. "Role of p53 in Human Cancers." In P53 - A Guardian of the Genome and Beyond [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.101961.
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TP53 codes tumor protein 53-p53 that controls the cell cycle through binding DNA directly and induces reversible cell-cycle arrest. The protein activates DNA repair genes if mutated DNA will be repaired or activates apoptotosis if the damaged DNA cannot be fixed. Therefore, p53, so-called the “guardian of the genome,” promote cell survival by allowing for DNA repair. However, the tumor-suppressor function of p53 is either lost or gained through mutations in half of the human cancers. In this work, functional perturbation of the p53 mechanism is elaborated at the breast, bladder, liver, brain, lung cancers, and osteosarcoma. Mutation of wild-type p53 not only diminishes tumor suppressor activity but transforms it into an oncogenic structure. Further, malfunction of the TP53 leads accumulation of additional oncogenic mutations in the cell genome. Thus, disruption of TP53 dependent survival pathways promotes cancer progression. This oncogenic TP53 promotes cell survival, prevents cell death through apoptosis, and contributes to the proliferation and metastasis of tumor cells. The purpose of this chapter is to discuss the contribution of mutant p53 to distinct cancer types.
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McNamara, John M., and Olof Leimar. "Central Concepts." In Game Theory in Biology, 13–26. Oxford University Press, 2020. http://dx.doi.org/10.1093/oso/9780198815778.003.0002.
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The chapter defines and discusses some of the central concepts in biological game theory. Strategies, which are rules for choosing actions as a function of state, play a pivotal role. It is explained how the theory operates at the level of strategies rather than attempting to follow the details of the underlying genetics that code for them. This is referred to as 'the phenotypic gambit', which is discussed and illustrated. The concept of the invasion fitness of a mutant strategy in a population that adopts another resident strategy is also central. This performance measure is used to give a necessary condition for evolutionary stability, formulated as the Nash equilibrium condition. It is explained how this stability condition can be reformulated in terms of simpler fitness proxies such as the mean lifetime number of offspring or the net rate of energy gain.
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Thompson, Gilbert R. "Familial hypercholesterolaemia." In Oxford Textbook of Endocrinology and Diabetes, 1667–73. Oxford University Press, 2011. http://dx.doi.org/10.1093/med/9780199235292.003.1240.
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Familial hypercholesterolaemia (OMIM 143890) is characterized by hypercholesterolaemia from birth, with the subsequent development of cutaneous and tendon xanthomas and premature onset of atherosclerosis, as first described by Müller over 70 years ago (1). Myant (2) noted that the monogenically determined increase in plasma cholesterol was largely confined to low-density lipoprotein (LDL) cholesterol and Goldstein and Brown (3) showed that the increase in LDL was due to mutations of the gene encoding the formation of LDL receptors, leading to defective catabolism of LDL. Over 1000 variations in the LDL receptor gene have now been described, most of which can cause familial hypercholesterolaemia (4). Usually only one mutant gene is inherited, which gives rise to the heterozygous form of the disease. Rarely, inheritance of two identical mutant alleles occurs, giving rise to homozygous familial hypercholesterolaemia. Inheritance of two mutations results in compound heterozygosity, which is clinically indistinguishable from genetically homozygous familial hypercholesterolaemia. The frequency of familial hypercholesterolaemia in the populations of Europe and North America averages 0.2%, but in some parts of the world it is much higher. Regions with an increased prevalence of familial hypercholesterolaemia include Lebanon, South Africa, and the Canadian province of Quebec. In each instance this is attributable to an unusually high frequency of one or two mutations within the population, such as the Lebanese allele, the Afrikaner 1 and 2 mutations, and the French Canadian allele. In South Africa and Canada the increased prevalence of familial hypercholesterolaemia represents a founder gene effect traceable to immigrant settlers from Europe, whereas in Muslim communities it reflects the frequency of first-cousin marriages. In notable contrast is the multiplicity of mutations found among familial hypercholesterolaemia patients in the UK, as shown in Fig. 12.2.2.1. An identical clinical syndrome to familial hypercholesterolaemia can occur as a result of inheritance of a mutation at the apoB locus, which results in a functionally defective form of LDL (5). This disorder, familial defective apoB-100 or FDB (OMIM 144010), has a frequency of 0.1% in people of European descent but has never been described in Japan. Rarely, familial hypercholesterolaemia is caused by dominantly inherited gain of function mutations of a gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) (OMIM 603776), which results in increased degradation of LDL receptors and an unusually severe clinical phenotype (6). It can also be caused by recessively inherited loss of function mutations of a gene encoding a protein involved in the clathrin-mediated internalization of the LDL receptor (6), which results in a milder phenotype than dominantly inherited forms of the condition and is known as autosomal recessive hypercholesterolaemia (OMIM 603813). A recent survey detected mutations of the LDL receptor, apoB, and PCSK9 genes in only 62% of patients with clinically definite familial hypercholesterolaemia (7), raising the likelihood that mutations of genes encoding other proteins involved in LDL metabolism remain to be discovered.
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Morales-Villegas, Enrique C., and Kausik K. Ray. "PCSK9 Inhibition with Evolocumab Reaching Physiologic LDL-C Levels for Reducing Atherosclerotic Burden and Cardiovascular Disease-The Full Landscape." In Frontiers in Cardiovascular Drug Discovery: Volume 4, 148–85. BENTHAM SCIENCE PUBLISHERS, 2019. http://dx.doi.org/10.2174/9781681083995118040007.
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Physiologically, in the presence of an intracellular deficit of cholesterol, the LDLR synthesis, expression and function increase, thus uptaking and providing cholesterol to the cell. This process is counter-regulated by PCSK9 expression, the protease inducing LDLR proteolysis, thereby limiting its function maintaining a constant cholesterol intracellular concentration. Accordingly, the balance between PCSK9 and LDLR regulates the intracellular concentration of cholesterol and in consequence has impact on circulating LDL-cholesterol. This chapter reviews the brief and amazing recent history with PCSK9 inhibition from basic science to current clinical recommendations for MAbs-PCSK9. In 2003 and 2005, respectively, the pcsk9 gene mutations, determinants of the “gain of function” of PCSK9 and severe hypercholesterolemia, and the pcsk9 gene mutations with “loss of function” of PCSK9, determinants of hypocholesterolemia were described; subsequently, in 2006, the association between the pcsk9 gene mutations and the “loss of function” of PCSK9 with hypocholesterolemia and reduction of up to 88% for the risk of a coronary event in the “mutant” population versus the control population was published. Since evolocumab clinical research program has completed and published their phases I, II and III results including its cardiovascular outcomes trial, this chapter is focused in reviewing the results of evolocumab clinical research program. In 2009, the effect of a “full human” monoclonal antibody vs PCSK9 in mice and non-human primates was first reported; MAb-PCSK9, AMG-145 (evolocumab) produced in cynomolgus monkeys a doubling in the number of LDLR and an average 75% reduction in circulating LDL-cholesterol. In 2012, the first phase I study with evolocumab versus placebo were reported; this program informed very significant reductions in LDLcholesterol in healthy subjects and patients with familial and non-familial hyper cholesterolemia treated without/with statins; tolerability and safety of evolocumab were similar to placebo. With this evidence, the phase II and III investigations with evolocumab initiated; four years later, the OSLER trial allowed us to envisage the following scenario: MAb-PCSK9 evolocumab have a favorable effect on LDLcholesterol, other apo-B100 lipoproteins and overall mortality and myocardial infarction; all the aforementioned with a very favorable safety and tolerability profile. In the same direction, in 2016 was published the GLAGOV trial, wich demonstrates for the first time that the addition of a non-statin therapy -evolocumab- to the optimal treatment with statins is associated with atheroregression; and finally, in 2017, the FOURIER and the EBBINGHAUS trials were presented, wich confirmed that the addition of evolocumab to the optimal treatment with statins is associated with an additional and significant 20% relative risk reduction -26 months of follow-up- for cardiovascular mortality, myocardial infarction and/or ischemic stroke, all without neurocognitive risk. Beyond the currently approved indications by regulatory agencies, considering the high cost of PCSK9 inhibitors and financial restraints within healthcare budgets, for now and before definitive and necessary cost-effectiveness analysis and price optimization are in place, evolocumab is recommended in specific clinical scenarios reviewed in this chapter.
Conference papers on the topic "Mutant p53 gain of function"
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Zhao, Yuhan, Cen Zhang, Xuetian Yue, Xiaoyan Li, Juan Liu, Haiyang Yu, Qifeng Yang, Zhaohui Feng, and Wenwei Hu. "Abstract 1221: Pontin, a new mutant p53 binding protein, promotes gain-of-function of mutant p53." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1221.
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Lozano, Guillermina. "Abstract SY07-03: Gain-of-function activities of mutant p53." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-sy07-03.
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Lozano, Guillermina. "Abstract SY04-01: The in vivo gain-of-function activities of mutant p53." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-sy04-01.
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Wei, Saisai, Sarah Malmut, Hongbo Wang, and Chunhong Yan. "Abstract 788: Effects of ATF3 on the gain-of-function of mutant p53." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-788.
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Guo, Xiaolan, Liyan Zhao, Hua Xiong, Kyle Auringer, Lei Wang, and Yibin Deng. "Abstract 1173: AKT-mTOR pathway mediates mutant p53 gain-of-function by inhibiting autophagy." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-1173.
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Redman-Rivera, Lindsay N., Timothy M. Shaver, Hailing Jin, Johanna M. Schafer, Quanhu Sheng, Rachel A. Hongo, Kathryn E. Beckermann, Brian D. Lehmann, Ferrin C. Wheeler, and Jennifer A. Pietenpol. "Abstract 2489: A functional genomics approach to determine mutant p53 gain-of-function mechanisms and phenotypes in tumorigenesis." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-2489.
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Martinez, Luis A., and Madhusudhan Kollareddy. "Abstract 2108: Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2108.
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Jo, Se-Young, Hae-Min Moon, ChuHee Lee, Se Jin Jang, and Young-Ah Suh. "Abstract A22: Cell growth regulation of gain-of-function mutant p53 via miRNAs on metabolic inhibition." In Abstracts: AACR Special Conference: Chromatin and Epigenetics in Cancer; September 24-27, 2015; Atlanta, GA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.chromepi15-a22.
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Jo, Se-Young, Hye-Min Moon, ChuHee Lee, Se Jin Jang, and Young-Ah Suh. "Abstract 2295: AMP-activated protein kinase (AMPK) signaling in the context of gain-of-function mutant p53 in vivo." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2295.
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Bado, Igor, Fotis Nikolos, Gayani Rajapaksa, Jan-Ake Gustafsson, and Christoforos Thomas. "Abstract 5043: ERβ decreases the invasiveness of triple-negative breast cancer cells by regulating mutant p53 gain-of-function." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5043.
Full textReports on the topic "Mutant p53 gain of function"
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Shieh, Sheau-Yann, and Xinbin CHen. Function of Wild-type and Mutant Forms of p53 in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, August 1997. http://dx.doi.org/10.21236/ada334430.
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Chamovitz, Daniel, and Albrecht Von Arnim. Translational regulation and light signal transduction in plants: the link between eIF3 and the COP9 signalosome. United States Department of Agriculture, November 2006. http://dx.doi.org/10.32747/2006.7696515.bard.
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The COP9 signalosome (CSN) is an eight-subunit protein complex that is highly conserved among eukaryotes. Genetic analysis of the signalosome in the plant model species Arabidopsis thaliana has shown that the signalosome is a repressor of light dependent seedling development as mutant Arabidopsis seedlings that lack this complex develop in complete darkness as if exposed to light. These mutant plants die following the seedling stage, even when exposed to light, indicating that the COP9 signalosome also has a central role in the regulation of normal photomorphogenic development. The biochemical mode of action of the signalosome and its position in eukaryotic cell signaling pathways is a matter of controversy and ongoing investigation, and recent results place the CSN at the juncture of kinase signaling pathways and ubiquitin-mediated protein degradation. We have shown that one of the many CSN functions may relate to the regulation of translation through the interaction of the CSN with its related complex, eukaryotic initiation factor (eIF3). While we have established a physical connection between eIF3 subunits and CSN subunits, the physiological and developmental significance of this interaction is still unknown. In an effort to understand the biochemical activity of the signalosome, and its role in regulating translation, we originally proposed to dissect the contribution of "h" subunit of eIF3 (eIF3h) along the following specific aims: (i) Isolation and phenotypic characterization of an Arabidopsis loss-of-function allele for eIF3h from insertional mutagenesis libraries; (ii) Creation of designed gain and loss of function alleles for eIF3h on the basis of its nucleocytoplasmic distribution and its yeast-two-hybrid interactions with other eIF3 and signalosome partner proteins; (iii) Determining the contribution of eIF3h and its interaction with the signalosome by expressing specific mutants of eIF3h in the eIF3h- loss-of function background. During the course of the research, these goals were modified to include examining the genetic interaction between csn and eif3h mutations. More importantly, we extended our effort toward the genetic analysis of mutations in the eIF3e subunit, which also interacts with the CSN. Through the course of this research program we have made several critical scientific discoveries, all concerned with the apparent diametrically opposed roles of eIF3h and eIF3e. We showed that: 1) While eIF3e is essential for growth and development, eIF3h is not essential for growth or basal translation; 2) While eIF3e has a negative role in translational regulation, eIF3h is positively required for efficient translation of transcripts with complex 5' UTR sequences; 3) Over-accumulation of eIF3e and loss-of-function of eIF3h both lead to cop phenotypes in dark-grown seedlings. These results were published in one publication (Kim et al., Plant Cell 2004) and in a second manuscript currently in revision for Embo J. Are results have led to a paradigm shift in translation research – eIF3 is now viewed in all systems as a dynamic entity that contains regulatory subuits that affect translational efficiency. In the long-term agronomic outlook, the proposed research has implications that may be far reaching. Many important plant processes, including developmental and physiological responses to light, abiotic stress, photosynthate, and hormones operate in part by modulating protein translation [23, 24, 40, 75]. Translational regulation is slowly coming of age as a mechanism for regulating foreign gene expression in plants, beginning with translational enhancers [84, 85] and more recently, coordinating the expression of multiple transgenes using internal ribosome entry sites. Our contribution to understanding the molecular mode of action of a protein complex as fundamental as eIF3 is likely to lead to advances that will be applicable in the foreseeable future.
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Casey, Therese, Sameer J. Mabjeesh, Avi Shamay, and Karen Plaut. Photoperiod effects on milk production in goats: Are they mediated by the molecular clock in the mammary gland? United States Department of Agriculture, January 2014. http://dx.doi.org/10.32747/2014.7598164.bard.
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US scientists, Dr. Theresa Casey and Dr. Karen Plaut, collaborated with Israeli scientists, Dr. SameerMabjeesh and Dr. AviShamay to conduct studies proposed in the BARD Project No. US-4715-14 Photoperiod effects on milk production in goats: Are they mediated by the molecular clock in the mammary gland over the last 3 years. CLOCK and BMAL1 are core components of the circadian clock and as heterodimers function as a transcription factor to drive circadian-rhythms of gene expression. Studies of CLOCK-mutant mice found impaired mammary development in late pregnancy was related to poor lactation performance post-partum. To gain a better understanding of role of clock in regulation of mammary development studies were conducted with the mammary epithelial cell line HC11. Decreasing CLOCK protein levels using shRNA resulted in increased mammary epithelial cell growth rate and impaired differentiation, with lower expression of differentiation markers including ad herens junction protein and fatty acid synthesis genes. When BMAL1 was knocked out using CRISPR-CAS mammary epithelial cells had greater growth rate, but reached stationary phase at a lower density, with FACS indicating cells were growing and dying at a faster rate. Beta-casein milk protein levels were significantly decreased in BMAL1 knockout cells. ChIP-seq analysis was conducted to identify BMAL1 target genes in mammary epithelial cells. Studies conducted in goats found that photoperiod duration and physiological state affected the dynamics of the mammary clock. Effects were likely independent of the photoperiod effects on prolactin levels. Interestingly, circadian rhythms of core body temperature, which functions as a key synchronizing cue sent out by the central clock in the hypothalamus, were profoundly affected by photoperiod and physiological state. Data support that the clock in the mammary gland regulates genes important to development of the gland and milk synthesis. We also found the clock in the mammary is responsive to changes in physiological state and photoperiod, and thus may serve as a mechanism to establish milk production levels in response to environmental cues.
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Fromm, Hillel, Paul Michael Hasegawa, and Aaron Fait. Calcium-regulated Transcription Factors Mediating Carbon Metabolism in Response to Drought. United States Department of Agriculture, June 2013. http://dx.doi.org/10.32747/2013.7699847.bard.
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Original objectives: The long-term goal of the proposed research is to elucidate the transcription factors, genes and metabolic networks involved in carbon metabolism and partitioning in response to water deficit. The proposed research focuses on the GTLcalcium/calmodulinbindingTFs and the gene and metabolic networks modulated by these TFs in Arabidopsis thaliana. The specific objectives are as follows. Objective-1 (USA): Physiological analyses of GTL1 loss- and gain-of-function plants under water sufficient and drought stress conditions Objective 2 (USA / Israel-TAU): Characterizion of GTL target genes and bioinformatic analysis of data to eulcidate gene-network topology. Objective-3 (Israel-TAU): Regulation of GTLmediated transcription by Ca²⁺/calmodulin: mechanism and biological significance. Objective-4 (Israel-BGU): Metabolic networks and carbon partitioning in response to drought. Additional direction: In the course of the project we added another direction, which was reported in the 2nd annual report, to elucidate genes controlling drought avoidance. The TAU team has isolated a few unhydrotropic (hyd) mutants and are in the process of mapping these mutations (of hyd13 and hyd15; see last year's report for a description of these mutants under salt stress) in the Arabidopsis genome by map-based cloning and deep sequencing. For this purpose, each hyd mutant was crossed with a wild type plant of the Landsberg ecotype, and at the F2 stage, 500-700 seedlings showing the unhydrotropic phenotype were collected separately and pooled DNA samples were subkected to the Illumina deep sequencing technology. Bioinformatics were used to identify the exact genomic positions of the mutations (based on a comparison of the genomic sequences of the two Arabidopsis thaliana ecotypes (Columbia and Landsberg). Background: To feed the 9 billion people or more, expected to live on Earth by the mid 21st century, the production of high-quality food must increase substantially. Based on a 2009 Declaration of the World Summit on Food Security, a target of 70% more global food production by the year 2050 was marked, an unprecedented food-production growth rate. Importantly, due to the larger areas of low-yielding land globally, low-yielding environments offer the greatest opportunity for substantial increases in global food production. Nowadays, 70% of the global available water is used by agriculture, and 40% of the world food is produced from irrigated soils. Therefore, much needs to be done towards improving the efficiency of water use by plants, accompanied by increased crop yield production under water-limiting conditions. Major conclusions, solutions and achievements: We established that AtGTL1 (Arabidopsis thaliana GT-2 LIKE1) is a focal determinant in water deficit (drought) signaling and tolerance, and water use efficiency (WUE). The GTL1 transcription factor is an upstream regulator of stomatal development as a transrepressor of AtSDD1, which encodes a subtilisin protease that activates a MAP kinase pathway that negatively regulates stomatal lineage and density. GTL1 binds to the core GT3 cis-element in the SDD1 promoter and transrepresses its expression under water-sufficient conditions. GTL1 loss-of-function mutants have reduced stomatal number and transpiration, and enhanced drought tolerance and WUE. In this case, higher WUE under water sufficient conditions occurs without reduction in absolute biomass accumulation or carbon assimilation, indicating that gtl1-mediated effects on stomatal conductance and transpiration do not substantially affect CO₂ uptake. These results are proof-of-concept that fine-tuned regulation of stomatal density can result in drought tolerance and higher WUE with maintenance of yield stability. Implications: Accomplishments during the IS-4243-09R project provide unique tools for continued discovery research to enhance plant drought tolerance and WUE.
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McClure, Michael A., Yitzhak Spiegel, David M. Bird, R. Salomon, and R. H. C. Curtis. Functional Analysis of Root-Knot Nematode Surface Coat Proteins to Develop Rational Targets for Plantibodies. United States Department of Agriculture, October 2001. http://dx.doi.org/10.32747/2001.7575284.bard.
Full textAbstract:
The goal of this research was to provide a better understanding of the interface between root-knot nematodes, Meloidogyne spp., and their host in order to develop rational targets for plantibodies and other novel methods of nematode control directed against the nematode surface coat (SC). Specific objectives were: 1. To produce additional monoclonal SC antibodies for use in Objectives 2, 3, and 4 and as candidates for development of plantibodies. 2. To determine the production and distribution of SC proteins during the infection process. 3. To use biochemical and immunological methods to perturbate the root-knot nematode SC in order to identify SC components that will serve as targets for rationally designed plantibodies. 4. To develop SC-mutant nematodes as additional tools for defining the role of the SC during infection. The external cuticular layer of nematodes is the epicuticle. In many nematodes, it is covered by a fuzzy material termed "surface coat" (SC). Since the SC is the outermost layer, it may playa role in the interaction between the nematode and its surroundings during all life stages in soil and during pathogenesis. The SC is composed mainly of proteins, carbohydrates (which can be part of glycoproteins), and lipids. SC proteins and glycoproteins have been labeled and extracted from preparasitic second-stage juveniles and adult females of Meloidogyne and specific antibodies have been raised against surface antigens. Antibodies can be used to gain more information about surface function and to isolate genes encoding for surface antigens. Characterization of surface antigens and their roles in different life-stages may be an important step towards the development of alternative control. Nevertheless, the role of the plant- parasitic nematode's surface in plant-nematode interaction is still not understood. Carbohydrates or carbohydrate-recognition domains (CROs) on the nematode surface may interact with CROs or carbohydrate molecules, on root surfaces or exudates, or be active after the nematode has penetrated into the root. Surface antigens undoubtedly play an important role in interactions with microorganisms that adhere to the nematodes. Polyclonal (PC) and monoclonal (MC) antibodies raised against Meloidogyne javanica, M. incognita and other plant-parasitic nematodes, were used to characterize the surface coat and secreted-excreted products of M. javanica and M. incognita. Some of the MC and PC antibodies raised against M. incognita showed cross-reactivity with the surface coat of M. javanica. Further characterization, in planta, of the epitopes recognized by the antibodies, showed that they were present in the parasitic juvenile stages and that the surface coat is shed during root penetration by the nematode and its migration between root cells. At the molecular level, we have followed two lines of experimentation. The first has been to identify genes encoding surface coat (SC) molecules, and we have isolated and characterized a small family of mucin genes from M. incognita. Our second approach has been to study host genes that respond to the nematode, and in particular, to the SC. Our previous work has identified a large suite of genes expressed in Lycopersicon esculentum giant cells, including the partial cDNA clone DB#131, which encodes a serine/threonine protein kinase. Isolation and predicted translation of the mature cDNA revealed a frame shift mutation in the translated region of nematode sensitive plants. By using primers homologous to conserved region of DB#131 we have identified the orthologues from three (nematode-resistant) Lycopersicon peruvianum strains and found that these plants lacked the mutation.