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https://www.readbyqxmd.com/read/28806777/a-synthetic-sickness-screen-for-senescence-re-engagement-targets-in-mutant-cancer-backgrounds
#1
Claire J Cairney, Lauren S Godwin, Alan E Bilsland, Sharon Burns, Katrina H Stevenson, Lynn McGarry, John Revie, Jon D Moore, Ceri M Wiggins, Rebecca S Collinson, Clare Mudd, Elpida Tsonou, Mahito Sadaie, Dorothy C Bennett, Masashi Narita, Christopher J Torrance, W Nicol Keith
Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28796261/p53-r273h-upregulates-neuropilin-2-to-promote-cell-mobility-and-tumor-metastasis
#2
Tao Lv, Xianqiang Wu, Lijuan Sun, Qingyong Hu, Yang Wan, Liang Wang, Zhiqiang Zhao, Xiao Tu, Zhi-Xiong Jim Xiao
Mounting evidence indicates that hotspot p53 mutant proteins often possess gain-of-function property in promoting cell mobility and tumor metastasis. However, the molecular mechanisms are not totally understood. In this study, we demonstrate that the hotspot mutation, p53-R273H, promotes cell migration, invasion in vitro and tumor metastasis in vivo. p53-R273H significantly represses expression of DLX2, a homeobox protein involved in cell proliferation and pattern formation. We show that p53-R273H-mediated DLX2 repression leads to upregulation of Neuropilin-2 (NRP2), a multifunctional co-receptor involved in tumor initiation, growth, survival and metastasis...
August 10, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28795426/blinded-histopathological-characterisation-of-pole-exonuclease-domain-mutant-endometrial-cancers-sheep-in-wolf-s-clothing
#3
Inge C Van Gool, Jef E H Ubachs, Ellen Stelloo, Cor D de Kroon, Jelle J Goeman, Vincent T H B M Smit, Carien L Creutzberg, Tjalling Bosse
AIMS: POLE exonuclease domain mutations identify a subset of endometrial cancer (EC) patients with an excellent prognosis. Implementation of this biomarker has been suggested to refine adjuvant treatment decisions, but the necessary sequencing is not widely performed and relatively expensive. Therefore, we aimed to identify histopathological and immunohistochemical characteristics to aid the detection of POLE-mutant ECs. METHODS AND RESULTS: Fifty-one POLE-mutant endometrioid, 67 POLE-wild-type endometrioid and 15 POLE-wild-type serous ECs were included (total N=133)...
August 10, 2017: Histopathology
https://www.readbyqxmd.com/read/28794016/serine-protease-inhibitor-serpinb2-binds-and-stabilizes-p21-in-senescent-cells
#4
Hsi-Hsien Hsieh, Ying-Chieh Chen, Jing-Ru Jhan, Jing-Jer Lin
SerpinB2 is a serine protease inhibitor that is also known as plasminogen activator inhibitor type 2 (PAI-2). It has been well documented that SerpinB2 is an inhibitor of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA). Interestingly, SerpinB2 level is increased in senescent cells and is considered a senescence biomarker. Through mimicking the elevated level of SerpinB2 in senescent cells, this study showed the proliferating human fibroblasts were induced into senescence. Senescence induced by SerpinB2 did not relate to its extracellular function as inhibition of SerpinB2 secretion, exogenous introduced SerpinB2, or a SerpinB2 mutant that failed to bind to its extracellular target uPA, did not have an effect on senescence...
August 9, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28790158/lung-tumors-with-distinct-p53-mutations-respond-similarly-to-p53-targeted-therapy-but-exhibit-genotype-specific-statin-sensitivity
#5
Frances K Turrell, Emma M Kerr, Meiling Gao, Hannah Thorpe, Gary J Doherty, Jake Cridge, David Shorthouse, Alyson Speed, Shamith Samarajiwa, Benjamin A Hall, Meryl Griffiths, Carla P Martins
Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear...
August 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28790110/replication-stress-leading-to-apoptosis-within-the-s-phase-contributes-to-synergism-between-vorinostat-and-azd1775-in-hnscc-harboring-high-risk-tp53-mutation
#6
Noriaki Tanaka, Ameeta A Patel, Lin Tang, Natalie L Silver, Antje Lindemann, Hideaki Takahashi, Roman Jaksik, Xiayu Rao, Nene N Kalu, Tseng-Cheng Chen, Jiping Wang, Mitchell J Frederick, Faye M Johnson, Frederico Gleber-Netto, Siqing Fu, Marek Kimmel, Jing Wang, Walter N Hittelman, Curtis R Pickering, Jeffrey N Myers, Abdullah A Osman
Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. Since mutation of TP53 in HNSCC occurs in 60-80% of non-HPV associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. <p>Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28777372/p53-inhibits-sp7-osterix-activity-in-the-transcriptional-program-of-osteoblast-differentiation
#7
Natalia Artigas, Beatriz Gámez, Mónica Cubillos-Rojas, Cristina Sánchez-de Diego, José Antonio Valer, Gabriel Pons, José Luis Rosa, Francesc Ventura
Osteoblast differentiation is achieved by activating a transcriptional network in which Dlx5, Runx2 and Osx/SP7 have fundamental roles. The tumour suppressor p53 exerts a repressive effect on bone development and remodelling through an unknown mechanism that inhibits the osteoblast differentiation programme. Here we report a physical and functional interaction between Osx and p53 gene products. Physical interaction was found between overexpressed proteins and involved a region adjacent to the OSX zinc fingers and the DNA-binding domain of p53...
August 4, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28775165/ezh2-palmitoylation-mediated-by-zdhhc5-in-p53-mutant-glioma-drives-malignant-development-and-progression
#8
Xueran Chen, Huihui Ma, Zhen Wang, Shangrong Zhang, Haoran Yang, Zhiyou Fang
Gilomas with mutant p53 occurring in 30% of giloma patients exhibit therapeutic resistance and poor outcomes. In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared to normal brain tissue and that this event to be tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y...
August 3, 2017: Cancer Research
https://www.readbyqxmd.com/read/28767065/do-multiwell-plate-high-throughput-assays-measure-loss-of-cell-viability-following-exposure-to-genotoxic-agents
#9
Razmik Mirzayans, Bonnie Andrais, David Murray
Cell-based assays in multiwell plates are widely used for radiosensitivity and chemosensitivity assessment with different mammalian cell types. Despite their relative ease of performance, such assays lack specificity as they do not distinguish between the cytostatic (reversible/sustained growth arrest) and cytotoxic (loss of viability) effects of genotoxic agents. We recently reported studies with solid tumor-derived cell lines demonstrating that radiosensitivity as measured by multiwell plate colorimetric (e...
August 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28765903/wild-type-p53-controls-the-level-of-fibronectin-expression-in-breast-cancer-cells
#10
Daeun You, Seung Pil Jung, Yisun Jeong, Soo Youn Bae, Sangmin Kim
Aberrant fibronectin (FN) expression is associated with poor prognosis, cell adhesion, and cell motility in a variety of cancer cells. In this study, we investigated the relationship between p53 and FN expression in breast cancer cells. Basal FN expression was significantly decreased by treatment with the p53 activator III, RITA, in MCF7 breast cancer cells with wild-type p53. In addition, overexpression of wild-type p53 markedly decreased the level of FN expression in p53-mutant breast cancer cells. To examine the mechanism underlying the relationship between p53 and FN expression, we treated MCF7 breast cancer cells with the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate)...
July 31, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28760853/survival-of-head-and-neck-cancer-cells-relies-upon-lzk-kinase-mediated-stabilization-of-mutant-p53
#11
Zoe C Edwards, Eleanor W Trotter, Pedro Torres-Ayuso, Phil Chapman, Henry M Wood, Katherine Nyswaner, John Brognard
Head and neck squamous cell carcinoma (HNSCC) includes epithelial cancers of the oral and nasal cavity, larynx, and pharynx and accounts for ~350,000 deaths/year worldwide. Smoking-related HNSCC is associated with few targetable mutations but is defined by frequent copy number alteration, the most common of which is gain at 3q. Critical 3q target genes have not been conclusively determined for HNSCC. Here we present data indicating that MAP3K13 (encoding LZK) is an amplified driver gene in HNSCC. Copy number gain at 3q resulted in increased MAP3K13 mRNA in HNSCC tumor samples and cell lines...
July 31, 2017: Cancer Research
https://www.readbyqxmd.com/read/28756138/mutant-p53-as-a-target-for-cancer-treatment
#12
REVIEW
Michael J Duffy, Naoise C Synnott, John Crown
TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers and squamous cell lung cancers, p53 is mutated in at least 80% of samples. Clearly, therefore, mutant p53 protein is an important candidate target against which new anticancer treatments could be developed...
July 27, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28754659/stress-induced-sleep-after-exposure-to-ultraviolet-light-is-promoted-by-p53-in-caenorhabditis-elegans
#13
Hilary DeBardeleben, Lindsey E Lopes, Mark P Nessel, David M Raizen
Stress-induced sleep (SIS) in C. elegans is important for restoration of cellular homeostasis and is a useful model to study the function and regulation of sleep. SIS is triggered when epidermal growth factor (EGF) activates the ALA neuron, which then releases neuropeptides to promote sleep. To further understand this behavior, we established a new model of stress-induced sleep using irradiation by ultraviolet C (UVC) light. While UVC irradiation requires ALA signaling and leads to a sleep state similar to that induced by heat and other stressors, it does not induce the proteostatic stress seen with heat exposure...
July 28, 2017: Genetics
https://www.readbyqxmd.com/read/28753207/the-proline-rich-domain-of-p53-is-dispensable-for-mgmt-dependent-dna-repair-and-cell-survival-following-alkylation-damage
#14
Katherine Baran, Mao Yang, Christopher P Dillon, Leona L Samson, Douglas R Green
In addition to promoting cell death and senescence, p53 also has important cellular survival functions. A mutant p53, lacking a proline-rich domain (p53(ΔP)), that is deficient in controlling both cell death and cell cycle arrest, was employed to determine the biological means by which p53 mediates survival upon DNA damage. While p53(ΔP) and p53(-/-) cells were equally resistant to many DNA damaging agents, p53(ΔP) cells showed an exquisite resistance to high doses of the alkylating agent Diazald (N-Methyl-N-(p-tolylsulfonyl)nitrosamide), as compared to cells completely deficient for p53 function...
July 28, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28749206/small-molecule-cb002-restores-p53-pathway-signaling-and-represses-colorectal-cancer-cell-growth
#15
Colby Richardson, Shengliang Zhang, Liz J Hernandez Borrero, Wafik S El-Deiry
Much effort is currently focused on the p53 pathway. p53 is a key tumor suppressor, which is mutated or lost in many human cancers. Restoration of the p53 pathway holds the potential to induce selective cell death in tumor cells without harming normal cells that have intact p53 pathways. Most tumor cells express mutated p53 or suppress p53 by overexpression of MDM2. In this study, a compound referred to as CB002 with one closely related compound from the Chembridge library were evaluated for tumor cytotoxicity without affecting normal cells by restoration of the p53 pathway...
July 27, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28749203/cb002-a-novel-p53-tumor-suppressor-pathway-restoring-small-molecule-induces-tumor-cell-death-through-the-pro-apoptotic-protein-noxa
#16
Liz J Hernandez-Borrero, Shengliang Zhang, Amriti Lulla, David T Dicker, Wafik S El-Deiry
P53 tumor suppressor gene mutations occur in the majority of human cancers and contribute to tumor development, progression and therapy resistance. Direct functional restoration of p53 as a transcription factor has been difficult to achieve in the clinic. We performed a functional screen using a bioluminescence-based transcriptional read-out to identify small molecules that restore the p53 pathway in mutant p53-bearing cancer cells. We identified CB002, as a candidate that restores p53 function in mutant p53-expressing colorectal cancer cells and without toxicity to normal human fibroblasts...
July 27, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28738256/p53-and-mitf-bcl-2-identified-as-key-pathways-in-the-acquired-resistance-of-nras-mutant-melanoma-to-mek-inhibition
#17
Ahmad Najem, Mohammad Krayem, François Salès, Nader Hussein, Bassam Badran, Caroline Robert, Ahmad Awada, Fabrice Journe, Ghanem E Ghanem
Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors...
July 21, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28735740/dna-damage-and-the-bystander-response-in-tumor-and-normal-cells-exposed-to-x-rays
#18
M Subhashree, R Venkateswarlu, K Karthik, V Shangamithra, P Venkatachalam
Monolayer and suspension cultures of tumor (BMG-1, CCRF-CEM), normal (AG1522, HADF, lymphocytes) and ATM-mutant (GM4405) human cells were exposed to X-rays at doses used in radiotherapy (high dose and high dose-rate) or radiological imaging (low dose and low dose-rate). Radiation-induced DNA damage, its persistence, and possible bystander effects were evaluated, based on DNA damage markers (γ-H2AX, p53(ser15)) and cell-cycle-specific cyclins (cyclin B1 and cyclin D1). Dose-dependent DNA damage and a dose-independent bystander response were seen after exposure to high dose and high dose-rate radiation...
September 2017: Mutation Research
https://www.readbyqxmd.com/read/28729028/micrornas-as-key-effectors-in-the-p53-network
#19
Frauke Goeman, Sabrina Strano, Giovanni Blandino
The guardian of the genome p53 is embedded in a fine-spun network of MicroRNAs. p53 is able to activate or repress directly the transcription of MicroRNAs that are participating in the tumor-suppressive mission of p53. On the other hand, the expression of p53 is under tight control of MicroRNAs that are either targeting directly p53 or factors that are modifying its protein level or activity. Although the most important function of p53 is suggested to be transcriptional regulation, there are several nontranscriptional functions described...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28726739/5-aza-2-2-difluroro-deoxycytidine-nuc013-a-novel-nucleoside-dna-methyl-transferase-inhibitor-and-ribonucleotide-reductase-inhibitor-for-the-treatment-of-cancer
#20
Richard Daifuku, Zhenbo Hu, Yogen Saunthararajah
Tumor suppressor genes can be silenced genetically as well as epigenetically. One approach to reversing epigenetic suppression of tumor suppressor genes is to inhibit DNA methyl transferase. 5-aza-2',2'-diflurorodeoxycytidine (NUC013) is a novel DNA methyl transferase and ribonucleotide reductase inhibitor that is a more potent inhibitor of growth than decitabine in the NCI 60 cancer cell line panel. NUC013 is more active than decitabine against p53-null/mutant cancer cell lines (p = 0.027) but is even more so against p53 wild-type (WT) cell lines (p = 0...
July 20, 2017: Pharmaceuticals
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