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https://www.readbyqxmd.com/read/28912527/treatment-with-caffeic-acid-and-resveratrol-alleviates-oxidative-stress-induced-neurotoxicity-in-cell-and-drosophila-models-of-spinocerebellar-ataxia-type3
#1
Yu-Ling Wu, Jui-Chih Chang, Wei-Yong Lin, Chien-Chun Li, Mingli Hsieh, Haw-Wen Chen, Tsu-Shing Wang, Chin-San Liu, Kai-Li Liu
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a polyglutamine (polyQ) repeat in the protein ataxin-3 which is involved in susceptibility to mild oxidative stress induced neuronal death. Here we show that caffeic acid (CA) and resveratrol (Res) decreased reactive oxygen species (ROS), mutant ataxin-3 and apoptosis and increased autophagy in the pro-oxidant tert-butyl hydroperoxide (tBH)-treated SK-N-SH-MJD78 cells containing mutant ataxin-3. Furthermore, CA and Res improved survival and locomotor activity and decreased mutant ataxin-3 and ROS levels in tBH-treated SCA3 Drosophila...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28910819/mechanisms-of-targeting-the-mdm2-p53-foxm1-axis-in-well-differentiated-intestinal-neuroendocrine-tumors
#2
Irina Grass, Franziska Briest, Dagmar Sedding, Markus Möbs, Friederike Christen, Joana Benecke, Karolin Fuchs, Daniel Kaemmerer, Stefanie Mende, Jörg Sänger, Almut Kunze, Christina Geisler, Helma Freitag, Florentine Lewens, Lina Worpenberg, Sara Iwaszkiewicz, Britta Siegmund, Wolfgang Walther, Michael Hummel, Patricia Grabowski
<br>Background/Aims: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of p53 negative regulators, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo. METHODS: By western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN...
September 14, 2017: Neuroendocrinology
https://www.readbyqxmd.com/read/28893683/sulfation-can-enhance-antitumor-activities-of-artemisia-sphaerocephala-polysaccharide-in-vitro-and-vivo
#3
Junlong Wang, Aijuan Bao, Qi Wang, Hongyun Guo, Yongdong Zhang, Junyu Liang, Weibao Kong, Jian Yao, Ji Zhang
In this study, a sulfated Artemisia sphaerocephala polysaccharide (ASPs) was prepared and its antitumor activity was evaluated in tumor cells and Hepatoma 22 (H22) tumor-bearing mice. In vitro experiments, ASPs significantly inhibited the growth of HepG2 and Hela cells with the IC50 values of 172.03 and 161.42μg/mL, respectively. Moreover, no direct cytotoxicity against mouse fibroblast L929 normal cells was observed in vitro. After oral administration for 12days, the tumor growth was significantly suppressed by ASPs at the doses of 200mg/kg (inhibition rate of 60...
September 8, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28887320/p53-gain-of-function-mutations-increase-cdc7-dependent-replication-initiation
#4
Arindam Datta, Dishari Ghatak, Sumit Das, Taraswi Banerjee, Anindita Paul, Ramesh Butti, Mahadeo Gorain, Sangeeta Ghuwalewala, Anirban Roychowdhury, Sk Kayum Alam, Pijush Das, Raghunath Chatterjee, Maitrayee Dasgupta, Chinmay Kumar Panda, Gopal C Kundu, Susanta Roychoudhury
Cancer-associated p53 missense mutants confer gain of function (GOF) and promote tumorigenesis by regulating crucial signaling pathways. However, the role of GOF mutant p53 in regulating DNA replication, a commonly altered pathway in cancer, is less explored. Here, we show that enhanced Cdc7-dependent replication initiation enables mutant p53 to confer oncogenic phenotypes. We demonstrate that mutant p53 cooperates with the oncogenic transcription factor Myb in vivo and transactivates Cdc7 in cancer cells...
September 8, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28887217/transcriptional-factors-eaf1-2-inhibit-endoderm-and-mesoderm-formation-via-suppressing-tgf-%C3%AE-signaling
#5
Jing-Xia Liu, Qin-Han Xu, Sen Li, XueDong Yu, WenYe Liu, Gang Ouyang, Ting Zhang, Ling-Ling Chen
Eaf family genes act in multiple cellular responses such as tumor suppression and embryonic development. In our previous work, Eaf1/2 was found to modulate convergence and extension (C&E) movements and pattern the embryonic anterior-posterior axis during zebrafish embryogenesis. Here, we found that loss-of-function of eaf1/2 caused expanded mesoderm and endoderm in zebrafish embryos and led to the recovery of endoderm specification in TGF-β factor-mzoep(tz257) mutants, while gain-of-function of eaf1/2 induced reduced mesoderm and endoderm...
September 5, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28874603/cancer-associated-arginine-to-histidine-mutations-confer-a-gain-in-ph-sensing-to-mutant-proteins
#6
Katharine A White, Diego Garrido Ruiz, Zachary A Szpiech, Nicolas B Strauli, Ryan D Hernandez, Matthew P Jacobson, Diane L Barber
The intracellular pH (pHi) of most cancers is constitutively higher than that of normal cells and enhances proliferation and cell survival. We found that increased pHi enabled the tumorigenic behaviors caused by somatic arginine-to-histidine mutations, which are frequent in cancer and confer pH sensing not seen with wild-type proteins. Experimentally raising the pHi increased the activity of R776H mutant epidermal growth factor receptor (EGFR-R776H), thereby increasing proliferation and causing transformation in fibroblasts...
September 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/28873303/discovery-of-novel-macrocyclic-hedgehog-pathway-inhibitors-acting-by-suppressing-the-gli-mediated-transcription
#7
Gang Liu, Wenjing Huang, Juan Wang, Xiaohua Liu, Jun Yang, Yu Zhang, Yong Geng, Wenfu Tan, Ao Zhang
A systemic medicinal chemistry campaign was conducted based on a literature hit compound 5 bearing the 4,5-dihydro-2H-benzo[b][1,5]oxazocin-6(3H)-one core through cyclization of two side substituents of the bicyclic skeleton combined with N-atom walking or ring-walking and the central ring expansion or extraction approaches, leading to several series of structurally unique tricyclic compounds. Among these, compound 29a was identified as the most potent against the hedgehog (Hh) signaling pathway showing an IC50 value of 23 nM...
September 5, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28872635/comprehensive-analyses-of-somatic-tp53-mutation-in-tumors-with-variable-mutant-allele-frequency
#8
Alexander J Cole, Ying Zhu, Trisha Dwight, Bing Yu, Kristie-Ann Dickson, Gregory B Gard, Jayne Maidens, Susan Valmadre, Anthony J Gill, Roderick Clifton-Bligh, Deborah J Marsh
Somatic mutation of the tumor suppressor gene TP53 is reported in at least 50% of human malignancies. Most high-grade serous ovarian cancers (HGSC) have a mutant TP53 allele. Accurate detection of these mutants in heterogeneous tumor tissue is paramount as therapies emerge to target mutant p53. We used a Fluidigm Access Array™ System with Massively Parallel Sequencing (MPS) to analyze DNA extracted from 76 serous ovarian tumors. This dataset has been made available to researchers through the European Genome-phenome Archive (EGA; EGAS00001002200)...
September 5, 2017: Scientific Data
https://www.readbyqxmd.com/read/28869450/idh1-status-is-significantly-different-between-high-grade-thalamic-and-superficial-gliomas
#9
Mingrong Zuo, Mao Li, Ni Chen, Tianping Yu, Bing Kong, Ruofei Liang, Xiang Wang, Qing Mao, Yanhui Liu
BACKGROUND: While major progress has been made in diagnosis and treatment of gliomas based on molecules, molecular features of thalamic glioma have rarely been reported till now. OBJECTIVE: IDH1 mutation is important for prognosis of gliomas and represents a distinctive category of glioma. We intended to survey specific molecular abnormalities in high-grade thalamic gliomas (WHO III-IV). METHODS: We collected data of 50 and 93 newly diagnosed high-grade thalamic and superficial glioma patients respectively and conducted a comparative analysis of molecular characteristics between them...
August 23, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28859621/nat10-is-upregulated-in-hepatocellular-carcinoma-and-enhances-mutant-p53-activity
#10
Qijiong Li, Xiaofeng Liu, Kemin Jin, Min Lu, Chunfeng Zhang, Xiaojuan Du, Baocai Xing
BACKGROUND: N-acetyltransferase 10 (NAT10) is a histone acetyltransferase which is involved in a wide range of cellular processes. Recent evidences indicate that NAT10 is involved in the development of human cancers. Previous study showed that NAT10 acetylates the tumor suppressor p53 and regulates p53 activation. As Tp53 gene is frequently mutated in hepatocellular carcinoma (HCC) and associates with the occurrence and development of HCC, the relationship between NAT10 and HCC was investigated in this study...
August 31, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28854261/gemcitabine-treatment-induces-endoplasmic-reticular-er-stress-and-subsequently-upregulates-urokinase-plasminogen-activator-upa-to-block-mitochondrial-dependent-apoptosis-in-panc-1-cancer-stem-like-cells-cscs
#11
Li Wang, Yi Zhang, Weiguo Wang, Yunjie Zhu, Yang Chen, Bole Tian
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates. The presence of cancer stem-like cells (CSCs) is believed to be among the underlying reasons for the aggressiveness of PDAC, which contributes to chemoresistance and recurrence. However, the mechanisms that induce chemoresistance and inhibit apoptosis remain largely unknown. METHODS: We used serum-free medium to enrich CSCs from panc-1 human pancreatic cancer cells and performed sphere formation testing, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and semi-quantitative western blotting to confirm the stemness of panc-1 CSCs...
2017: PloS One
https://www.readbyqxmd.com/read/28853613/lung-endothelial-microrna-1-regulates-tumor-growth-and-angiogenesis
#12
Asawari Korde, Lei Jin, Jian-Ge Zhang, Anuradha Ramaswamy, Buqu Hu, Saeed Kolahian, Brenda Juan Guardela, Jose Herazo-Maya, Jill M Siegfried, Laura Stabile, Margaret A Pisani, Roy S Herbst, Naftali Kaminski, Jack A Elias, Jonathan T Puchalski, Shervin S Takyar
RATIONALE: VEGF down-regulates miR-1 in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. OBJECTIVES: To examine the clinical significance of miR-1 in NSCLC and its specific role in tumor endothelium. Method and measurements: MiR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used VE-cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse...
August 30, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28852847/distinct-molecular-profile-of-diffuse-cerebellar-gliomas
#13
Masashi Nomura, Akitake Mukasa, Genta Nagae, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shiro Fukuda, Takayoshi Umeda, Tomonari Suzuki, Ryohei Otani, Keiichi Kobayashi, Takashi Maruyama, Shota Tanaka, Shunsaku Takayanagi, Takahide Nejo, Satoshi Takahashi, Koichi Ichimura, Taishi Nakamura, Yoshihiro Muragaki, Yoshitaka Narita, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Junji Shibahara, Hiroyuki Aburatani, Nobuhito Saito
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions...
August 29, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28846075/dysfunction-of-the-mdm2-p53-axis-is-linked-to-premature-aging
#14
Davor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K Alwasiyah, Bidisha Saha, Fuki M Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R Tong, Chen Katz, George M Martin, Junko Oshima, Carol Prives, Christian Kubisch
The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome...
August 28, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28842590/ddx3-localizes-to-the-centrosome-and-prevents-multipolar-mitosis-by-epigenetically-and-translationally-modulating-p53-expression
#15
Wei-Ju Chen, Wei-Ting Wang, Tsung-Yuan Tsai, Hao-Kang Li, Yan-Hwa Wu Lee
The DEAD-box RNA helicase DDX3 plays divergent roles in tumorigenesis, however, its function in mitosis is unclear. Immunofluorescence indicated that DDX3 localized to centrosome throughout the cell cycle and colocalized with centrosome-associated p53 during mitosis in HCT116 and U2OS cells. DDX3 depletion promoted chromosome misalignment, segregation defects and multipolar mitosis, eventually leading to G2/M delay and cell death. DDX3 prevented multipolar mitosis by inactivation and coalescence of supernumerary centrosomes...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28842295/macrophage-heme-oxygenase-1-sirt1-p53-axis-regulates-sterile-inflammation-in-liver-ischemia-reperfusion-injury
#16
Kojiro Nakamura, Min Zhang, Shoichi Kageyama, Bibo Ke, Takehiro Fujii, Rebecca A Sosa, Elaine F Reed, Nakul Datta, Ali Zarrinpar, Ronald W Busuttil, Jesus A Araujo, Jerzy W Kupiec-Weglinski
BACKGROUND &AIMS: Hepatic ischemia-reperfusion injury (IRI), an exogenous antigen-independent local inflammation and hepatocellular death, represents a risk factor for acute and chronic rejection in liver transplantation. METHODS: To gain insights into molecular communication in the mechanism of liver IRI, we analyzed human liver transplants in parallel with primary murine macrophage cell cultures and IR-stressed livers in myeloid-specific HO-1 (heme oxygenase-1) gene mutant mice for anti-inflammatory and cytoprotective functions of macrophage-specific HO-1 / SIRT1 (sirtuin 1) / p53 (tumor suppressor protein) signaling RESULTS: Decreased HO-1 expression in human post-reperfusion liver transplant biopsies correlated with deteriorated hepatocellular function (serum ALT; p<0...
August 23, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28839193/the-epigenetic-modifier-fam208a-is-required-to-maintain-epiblast-cell-fitness
#17
Shohag Bhargava, Brian Cox, Christiana Polydorou, Veronika Gresakova, Vladimir Korinek, Hynek Strnad, Radislav Sedlacek, Trevor Allan Epp, Kallayanee Chawengsaksophak
Gastrulation initiates with the formation of the primitive streak, during which, cells of the epiblast delaminate to form the mesoderm and definitive endoderm. At this stage, the pluripotent cell population of the epiblast undergoes very rapid proliferation and extensive epigenetic programming. Here we show that Fam208a, a new epigenetic modifier, is essential for early post-implantation development. We show that Fam208a mutation leads to impaired primitive streak elongation and delayed epithelial-to-mesenchymal transition...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28838997/lack-of-constitutively-active-dna-repair-sensitizes-glioblastomas-to-akt-inhibition-and-induces-synthetic-lethality-with-radiation-treatment-in-a-p53-dependentmanner
#18
Kamalakannan Palanichamy, Disha Patel, John R Jacob, Kevin T Litzenberg, Nicolaus Gordon, Kirstin Acus, Shin-Ei Noda, Arnab Chakravarti
Treatment refractory glioblastoma (GBM) remains a major clinical problem globally and targeted therapies in GBM have not been promising to date. TCGA integrative analysis of GBM reported the striking finding of genetic alterations in the p53 and PI3K pathways in over 80% of GBMs. Given the role of these pathways in making cell-fate decisions and responding to genotoxic stress, we investigated the reliance of these two pathways in mediating radiation-resistance. We selected a panel of GBM cell lines and glioma stem cells (GSC) with wild-type TP53 (p53-wt) and mutant TP53, mutations known to interfere with p53 functionality (p53-mt)...
August 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28837154/akt2-suppresses-pro-survival-autophagy-triggered-by-dna-double-strand-breaks-in-colorectal-cancer-cells
#19
Nina Seiwert, Carina Neitzel, Svenja Stroh, Teresa Frisan, Marc Audebert, Mahmoud Toulany, Bernd Kaina, Jörg Fahrer
DNA double-strand breaks (DSBs) are critical DNA lesions, which threaten genome stability and cell survival. DSBs are directly induced by ionizing radiation (IR) and radiomimetic agents, including the cytolethal distending toxin (CDT). This bacterial genotoxin harbors a unique DNase-I-like endonuclease activity. Here we studied the role of DSBs induced by CDT and IR as a trigger of autophagy, which is a cellular degradation process involved in cell homeostasis, genome protection and cancer. The regulatory mechanisms of DSB-induced autophagy were analyzed, focusing on the ATM-p53-mediated DNA damage response and AKT signaling in colorectal cancer cells...
August 24, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28836764/intrinsic-differences-in-backbone-dynamics-between-wild-type-and-dna-contact-mutants-of-the-p53-dna-binding-domain-revealed-by-nuclear-magnetic-resonance-spectroscopy
#20
Juhi A Rasquinha, Aritra Bej, Shraboni Dutta, Sujoy Mukherjee
Mutations in p53's DNA binding domain (p53DBD) are associated with 50% of all cancers, making it an essential system to investigate and understand the genesis and progression of cancer. In this work, we studied the changes in the structure and dynamics of wild type p53DBD in comparison with two of its "hot-spot" DNA-contact mutants, R248Q and R273H, by analysis of backbone amide chemical shift perturbations and (15)N spin relaxation measurements. The results of amide chemical shift changes indicated significantly more perturbations in the R273H mutant than in wild type and R248Q p53DBD...
September 7, 2017: Biochemistry
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