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https://www.readbyqxmd.com/read/29236321/murine-models-of-osteosarcoma-a-piece-of-the-translational-puzzle
#1
Mannu K Walia, Wilson Castillo-Tandazo, Anthony J Mutsaers, T John Martin, Carl R Walkley
Osteosarcoma (OS) is the most common cancer of bone in children and young adults. Despite extensive research efforts, there has been no significant improvement in patient outcome for many years. An improved understanding of the biology of this cancer and how genes frequently mutated contribute to OS may help improve outcomes for patients. Whilst our knowledge of the mutational burden of OS is approaching saturation, our understanding of how these mutations contribute to OS initiation and maintenance is less clear...
December 13, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29236030/the-tumor-suppressor-p53-in-mucosal-melanoma-of-the-head-and-neck
#2
REVIEW
Marie Kristin Fritsche, Andreas Knopf
Despite worldwide prevention programs, the incidence for cutaneous melanoma is continuously increasing. Mucosal melanoma (MM) represents a rare but highly aggressive phenotype of common melanoma with predilection in the sinonasal system. Far away from ultraviolet sun exposure, the molecular mechanisms underlying tumorigenesis and the highly aggressive clinical behavior are poorly understood. In many solid malignomas of the head and neck region, p53 tumor suppressor functions as oncogene due to p53 protein stabilizing mutation...
December 13, 2017: Genes
https://www.readbyqxmd.com/read/29235570/targeting-negative-regulation-of-p53-by-mdm2-and-wip1-as-a-therapeutic-strategy-in-cutaneous-melanoma
#3
Chiao-En Wu, Arman Esfandiari, Yi-Hsuan Ho, Nan Wang, Ahmed Khairallah Mahdi, Erhan Aptullahoglu, Penny Lovat, John Lunec
BACKGROUND: Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2830371, and MDM2-p53 binding antagonists (nutlin-3, RG7388 and HDM201) alone and in combination treatment in cutaneous melanoma cell lines and explored the mechanistic basis of these responses in relation to the genotype and induced gene expression profile of the cells...
December 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29233839/genetics-of-tumors-of-the-adrenal-cortex
#4
Fidéline Bonnet-Serrano, Jerome Bertherat
This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD) which can be sporadic or part of Carney complex, and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of tumors suggests the existence of an underlying genetic predisposition...
December 12, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29232465/new-treatments-in-ovarian-cancer
#5
E Pujade-Lauraine
In targeting DNA repair pathways of the most genomic instable cancer, poly-(adenosine diphosphate [ADP])-ribose polymerase inhibitors (PARPi) have been demonstrated as the most effective drug since platinum in high grade serous or endometrioid ovarian cancer. Immunotherapy is strongly pushing the door of ovarian cancer and has the ambition to change the fate of this deadly disease when combined with chemotherapy, vascular endothelial growth factor inhibitor or PARPi. The activity of PARPi could also be improved by modulators of the cell cycle, which are required to give time enough for DNA repair...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29229990/tumor-suppressor-p53-links-ceramide-metabolism-to-dna-damage-response-through-alkaline-ceramidase-2
#6
Ruijuan Xu, Monica Garcia-Barros, Sally Wen, Fang Li, Chih-Li Lin, Yusuf A Hannun, Lina M Obeid, Cungui Mao
p53 mediates the DNA damage response (DDR) by regulating the expression of genes implicated in cell cycle arrest, senescence, programmed cell death (PCD), and metabolism. Herein we demonstrate that human alkaline ceramidase 2 (ACER2) is a novel transcriptional target of p53 and that its transactivation by p53 mediates the DDR. We found that p53 overexpression or its activation by ionizing radiation (IR) upregulated ACER2 in cells. Two putative p53 responsive elements (p53REs) were found in its first intron of the ACER2 gene, and Chromatin Immunoprecipitation (ChIP) assays in combination with promoter activity assays demonstrated that these p53REs are the bona fide p53 binding sites that mediate ACER2 transactivation by p53...
December 11, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29225165/cross-talk-between-tp53-and-c-myc-in-the-pathophysiology-of-diamond-blackfan-anemia-evidence-from-rpl11-deficient-in-vivo-and-in-vitro-models
#7
Anirban Chakraborty, Tamayo Uechi, Yukari Nakajima, Hanna T Gazda, Marie-Françoise O'Donohue, Pierre-Emmanuel Gleizes, Naoya Kenmochi
Mutations in genes encoding ribosomal proteins have been identified in Diamond-Blackfan anemia (DBA), a rare genetic disorder that presents with a prominent erythroid phenotype. TP53 has been implicated in the pathophysiology of DBA with ribosomal protein (RP) L11 playing a crucial role in the TP53 response. Interestingly, RPL11 also controls the transcriptional activity of c-Myc, an oncoprotein that positively regulates ribosome biogenesis. In the present study, we analyzed the consequences of rpl11 depletion on erythropoiesis and ribosome biogenesis in zebrafish...
December 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29225033/mutant-p53-gains-its-function-via-c-myc-activation-upon-cdk4-phosphorylation-at-serine-249-and-consequent-pin1-binding
#8
Peng Liao, Shelya X Zeng, Xiang Zhou, Tianjian Chen, Fen Zhou, Bo Cao, Ji Hoon Jung, Giannino Del Sal, Shiwen Luo, Hua Lu
TP53 missense mutations significantly influence the development and progression of various human cancers via their gain of new functions (GOF) through different mechanisms. Here we report a unique mechanism underlying the GOF of p53-R249S (p53-RS), a p53 mutant frequently detected in human hepatocellular carcinoma (HCC) that is highly related to hepatitis B infection and aflatoxin B1. A CDK inhibitor blocks p53-RS's nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cells, phosphorylates it, and enhances its nuclear localization...
November 23, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29223537/rankl-signaling-sustains-primary-tumor-growth-in-genetically-engineered-mouse-models-of-lung-adenocarcinoma
#9
Julien Faget, Caroline Contat, Nadine Zangger, Solange Peters, Etienne Meylan
HYPOTHESIS: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-κB (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy. METHODS: RANK and RANKL expression in human lung adenocarcinoma was interrogated from publicly available gene expression datasets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using micro-computed tomography...
December 6, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29218546/establishing-cut-off-points-with-clinical-relevance-for-bcl-2-cyclin-d1-p16-p21-p27-p53-sox11-and-wt1-expression-in-glioblastoma-a-short-report
#10
Emma Camacho-Urkaray, Jorge Santos-Juanes, Francisco Borja Gutiérrez-Corres, Beatriz García, Luis M Quirós, Isabel Guerra-Merino, José Javier Aguirre, Iván Fernández-Vega
PURPOSE: Glioblastoma (GBM) ranks among the most challenging cancers to treat and there is an urgent need for clinically relevant prognostic and diagnostic biomarkers. Here, we set out to investigate the expression of eight proteins (bcl-2, cyclin D1, p16, p21, p27, p53, Sox11 and WT1) in GBM with the specific aim to establish immunohistochemistry cut-off points with clinical relevance. METHODS: Immunohistochemistry (IHC) was used to examine protein expression in 55 surgical GBM specimens using H-scores, and IHC cut-off points were established using the Cutoff Finder web platform...
December 7, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/29218508/use-of-huh6-and-other-human-derived-hepatoma-lines-for-the-detection-of-genotoxins-a-new-hope-for-laboratory-animals
#11
Monika Waldherr, Miroslav Mišík, Franziska Ferk, Jana Tomc, Bojana Žegura, Metka Filipič, Wolfgang Mikulits, Sören Mai, Oskar Haas, Wolfgang W Huber, Elisabeth Haslinger, Siegfried Knasmüller
Cell lines which are currently used in genotoxicity tests lack enzymes which activate/detoxify mutagens. Therefore, rodent-derived liver preparations are used which reflect their metabolism in humans only partly; as a consequence misleading results are often obtained. Previous findings suggest that certain liver cell lines express phase I/II enzymes and detect promutagens without activation; however, their use is hampered by different shortcomings. The aim of this study was the identification of a suitable cell line...
December 7, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29216252/global-computational-mutagenesis-provides-a-critical-stability-framework-in-protein-structures
#12
Caitlyn L McCafferty, Yuri V Sergeev
A protein's amino acid sequence dictates the folds and final structure the macromolecule will form. We propose that by identifying critical residues in a protein's atomic structure, we can select a critical stability framework within the protein structure essential to proper protein folding. We use global computational mutagenesis based on the unfolding mutation screen to test the effect of every possible missense mutation on the protein structure to identify the residues that cannot tolerate a substitution without causing protein misfolding...
2017: PloS One
https://www.readbyqxmd.com/read/29209894/mitochondrial-energy-metabolism-and-signalling-in-human-glioblastoma-cell-lines-with-different-pten-gene-status
#13
Marina Comelli, Ivan Pretis, Alessia Buso, Irene Mavelli
Glioblastomas epidemiology and aggressiveness demand for a well characterization of biochemical mechanisms of the cells. The discovery of oxidative tumours related to chemoresistance is changing the prevalent view of dysfunctional mitochondria in cancer cells. Thus, glioblastomas metabolism is now an area of intense research, wherein was documented a high heterogeneity in energy metabolism and in particular in mitochondrial OxPhos. We report results gained by investigating mitochondrial OxPhos and bioenergetics, in a model of three human glioblastoma cell lines characterized by a different PTEN gene status...
December 6, 2017: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/29207594/cancer-mutated-ribosome-protein-l22-rpl22-el22-suppresses-cancer-cell-survival-by-blocking-p53-mdm2-circuit
#14
Bo Cao, Ziling Fang, Peng Liao, Xiang Zhou, Jianping Xiong, Shelya Zeng, Hua Lu
Several ribosomal proteins (RPs) in response to various ribosomal stressors have been shown to play a critical role in p53-dependent regulation of cell cycle arrest, apoptosis and tumor suppression. Here, we report ribosomal protein L22 (RPL22/eL22) as a novel p53 activator highly mutated (mostly deletion mutation) in various types of human cancers, but not essential for ribosomal biogenesis in normal cells. Ectopic expression of RPL22/eL22 suppressed the colony formation of cancer cells in a p53-dependent manner, whereas knockdown of RPL22/eL22 significantly compromised p53 activation by Actinomycin D, rescuing p53-induced G1/G0 cell cycle arrest...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207182/antitumor-activity-of-the-synthetic-retinoid-st1926-on-primary-effusion-lymphoma-in-vitro-and-in-vivo-models
#15
Louna Karam, Bilal Houshaymi, Rana Abdel-Samad, Mariam Jaafar, Iman Halloum, Claudio Pisano, Frank Neipel, Nadine Darwiche, Raghida Abou Merhi
Primary effusion lymphoma (PEL) is a rare B-cell neoplasm, associated with Kaposi sarcoma-associated herpes virus/human herpes virus-8 (KSHV/HHV-8), arising as malignant effusions in body cavities. PEL cells do not harbor conventional genetic cancer mutations; however, their oncogenesis is mainly attributed to HHV-8 latent genes. Treatment strategies are inefficient resulting in poor prognosis of PEL patients, stressing the need for new effective therapy. ST1926 is a synthetic retinoid with favorable antitumor properties and no cross-resistance with the natural retinoid, all-trans retinoic acid...
December 5, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29203914/synthetically-lethal-nanoparticles-for-treatment-of-endometrial-cancer
#16
Kareem Ebeid, Xiangbing Meng, Kristina W Thiel, Anh-Vu Do, Sean M Geary, Angie S Morris, Erica L Pham, Amaraporn Wongrakpanich, Yashpal S Chhonker, Daryl J Murry, Kimberly K Leslie, Aliasger K Salem
Uterine serous carcinoma, one of the most aggressive types of endometrial cancer, is characterized by poor outcomes and mutations in the tumour suppressor p53. Our objective was to engender synthetic lethality to paclitaxel (PTX), the frontline treatment for endometrial cancer, in tumours with mutant p53 and enhance the therapeutic efficacy using polymeric nanoparticles (NPs). First, we identified the optimal NP formulation through comprehensive analyses of release profiles and cellular-uptake and cell viability studies...
December 4, 2017: Nature Nanotechnology
https://www.readbyqxmd.com/read/29203787/crispr-cas9-derived-models-of-ovarian-high-grade-serous-carcinoma-targeting-brca1-pten-and-nf1-and-correlation-with-platinum-sensitivity
#17
Josephine B Walton, Malcolm Farquharson, Susan Mason, Jennifer Port, Bjorn Kruspig, Suzanne Dowson, David Stevenson, Daniel Murphy, Martin Matzuk, Jaeyeon Kim, Seth Coffelt, Karen Blyth, Iain A McNeish
Transplantable murine models of ovarian high grade serous carcinoma (HGSC) remain an important research tool. We previously showed that ID8, a widely-used syngeneic model of ovarian cancer, lacked any of the frequent mutations in HGSC, and used CRISPR/Cas9 gene editing to generate derivatives with deletions in Trp53 and Brca2. Here we have used one ID8 Trp53 -/- clone to generate further mutants, with additional mutations in Brca1, Pten and Nf1, all of which are frequently mutated or deleted in HGSC. We have also generated clones with triple deletions in Trp53, Brca2 and Pten...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29200721/helichrysetin-induces-dna-damage-that-triggers-jnk-mediated-apoptosis-in-ca-ski-cells
#18
Ho Yen Fong, Sri Nurestri Abd Malek, Hui Shin Yee, Saiful Anuar Karsani
Background: Cervical cancer has become one of the most common cancers in women and currently available treatment options for cervical cancer are very limited. Naturally occurring chalcones and its derivatives have been studied extensively as a potential anticancer agent in different types of cancer and helichrysetin is naturally occurring chalcone that possess potent antiproliferative activity toward human cancer cells. Materials and Methods: Inhibitory activity of helichrysetin was evaluated at different concentrations...
October 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/29198328/the-role-of-nuclear-factor-kappa-b-signaling-in-human-cervical-cancer
#19
REVIEW
Sam Tilborghs, Jerome Corthouts, Yannick Verhoeven, David Arias, Christian Rolfo, Xuan Bich Trinh, Peter A van Dam
Background The Nuclear Factor kappaB (NF-kB) family consists of transcription factors that play a complex and essential role in the regulation of immune responses and inflammation. NF-kB has recently generated considerable interest as it has been implicated in human cancer initiation, progression and resistance to treatment. In the present comprehensive review the different aspects of NF-kB signaling in the carcinogenesis of cancer of the uterine cervix are discussed. NF-kB functions as part of a network, which determines the pattern of its effects on the expression of several other genes (such as crosstalks with reactive oxygen species, p53, STAT3 and miRNAS) and thus its function...
December 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29195118/deciphering-p53-signaling-in-tumor-suppression
#20
REVIEW
Stephano S Mello, Laura D Attardi
The p53 transcription factor is mutated in over half of human cancers, and p53-null mice are highly predisposed to cancer, highlighting p53s essential role in tumor suppression. Studies in mouse models have revealed that p53 cell cycle arrest and apoptosis responses to acute DNA damage signals are dispensable for tumor suppression, prompting a search for new mechanisms underlying p53-mediated cancer suppression. p53 responds to other types of stress signals and regulates a host other cellular processes, including maintenance of genomic stability, metabolism, stemness, non-apoptotic cell death, migration/invasion, and cell signaling, any or all of which could be fundamental for suppressing carcinogenesis...
November 28, 2017: Current Opinion in Cell Biology
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