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p53 mdm2

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https://www.readbyqxmd.com/read/28425639/designing-dual-inhibitors-of-mdm2-mdmx-unexpected-coupling-of-water-with-gatekeeper-y100-99
#1
Xiong An Lee, Chandra Verma, Adelene Y L Sim
Mdm2 and MdmX share high structural similarity in their N-terminal domains, yet dual inhibitors are challenging to design due to differences in the conformations of the binding pockets, and notably of the proposed gatekeeper residue, Y100/99. Analysis of crystal structures and molecular dynamics (MD) simulations of complexes of Mdm2 and MdmX resulted in the identification of a water molecule with a long residence time that appears to be modulated by the conformation of Y100/99. These observations lead us to speculate that dual inhibitors either i) stabilize both Mdm2 and MdmX with Y100/99 in the open conformation typically seen in complexes of Mdm2 with p53, or ii) the dual inhibitors are agnostic to the conformation of Y100/99...
April 20, 2017: Proteins
https://www.readbyqxmd.com/read/28415963/impact-of-the-mdm2-splice-variants-mdm2-a-mdm2-b-and-mdm2-c-on-cytotoxic-stress-response-in-breast-cancer-cells
#2
Johanna Huun, Liv B Gansmo, Bård Mannsåker, Gjertrud Titlestad Iversen, Jan Inge Øvrebø, Per E Lønning, Stian Knappskog
BACKGROUND: The murine double minute 2 (MDM2) is an oncogene and a negative regulator of the tumor suppressor protein p53. MDM2 is known to be amplified in numerous human cancers, and upregulation of MDM2 is considered to be an alternative mechanism of p53 inactivation. The presence of many splice variants of MDM2 has been observed in both normal tissues and malignant cells; however their impact and functional properties in response to chemotherapy treatment are not fully understood. Here, we investigate the biological effects of three widely expressed alternatively spliced variants of MDM2; MDM2-A, MDM2-B and MDM2-C, both in unstressed MCF-7 breast cancer cells and in cells subjected to chemotherapy...
April 17, 2017: BMC Cell Biology
https://www.readbyqxmd.com/read/28414026/targeting-oct2-and-p53-formononetin-prevents-cisplatin-induced-acute-kidney-injury
#3
Di Huang, Chuangyuan Wang, Yingjie Duan, Qiang Meng, Zhihao Liu, Xiaokui Huo, Huijun Sun, Xiaodong Ma, Kexin Liu
Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment...
April 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28408319/deriving-and-testing-of-dysplastic-murine-hepatocytes-a-new-platform-in-liver-cancer-research
#4
Sharon Pok, Harpreet Vohra, Charbel Wehbe, Vanessa A Barn, Evi Arfianti, Yock-Young Dan, Geoffrey C Farrell, Narci C Teoh
Dysplastic hepatocytes(DH) represent altered hepatocytes with potential for malignant transformation. To date, most research on pathways to hepatocarcinogenesis has focused on use of "hepatoma" cell-lines derived from hepatocellular carcinoma(HCC). We describe a novel technique for deriving/culturing DH and demonstrate their utility for functional studies in vitro, compared to primary hepatocytes(PH) and HCC. PH and DH were prepared by portal vein collagenase perfusion from C57BL/6J mice. DH were subsequently subjected to FACS...
April 10, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28407576/hotair-may-regulate-proliferation-apoptosis-migration-and-invasion-of-mcf-7-cells-through-regulating-the-p53-akt-jnk-signaling-pathway
#5
Yang Yu, Feng Lv, Dong Liang, Qinheng Yang, Bin Zhang, Hong Lin, Xiaofang Wang, Guo Qian, Jinzhong Xu, Wei You
Breast cancer is a common malignancy, and it is the second leading cause of cancer-related death among women worldwide. The pathogenesis of breast cancer is poorly understood, leading to unsatisfactory efficacy of current anti-PC therapies. The aim of this study is to investigate the role of LncRNA HOTAIR in proliferation, apoptosis, migration and invasion of human breast cancer cell line MCF-7. MCF-7 cells were cultured and transfected with HOTAIR siRNA, and the proliferation rate of cells was determined using MTT and colony-forming assay; moreover, the apoptosis as well as cell cycles were determined using annexin V/propidium iodide staining methods and analyzed using flow cytometery; furthermore, cell scratch and transwell assays have been performed to examine the migration and invasion of MCF-7 cells; Next, cells were collected, and RT-qPCR as well as western blotting assay were performed to examine the expression of P53, MDM2, AKT, JNK, MMP-2 and MMP-9...
April 10, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28406729/stabilization-of-the-p53-dna-complex-by-the-nuclear-protein-dmp1%C3%AE
#6
Robert D Kendig, Fumitake Kai, Elizabeth A Fry, Kazushi Inoue
We recently reported the existence of a physical interaction between the Myb-like transcription factor Dmp1 (Dmtf1) and p53 in which Dmp1 antagonized polyubiquitination of p53 by Mdm2 and promoted its nuclear localization. Dmp1 significantly stabilized p53-DNA complexes on promoters that contained p53-consensus sequences, which were either supershifted or disrupted with antibodies to Dmp1. Lysates from mice injected with doxorubicin showed that Dmp1 bound to p21(Cip1), Bbc3, and Thbs1 gene regulatory regions in a p53-dependent fashion...
April 13, 2017: Cancer Investigation
https://www.readbyqxmd.com/read/28406480/wdr79-promotes-the-proliferation-of-non-small-cell-lung-cancer-cells-via-usp7-mediated-regulation-of-the-mdm2-p53-pathway
#7
Yang Sun, Lanqin Cao, Xunan Sheng, Jieying Chen, Yu Zhou, Chao Yang, Tanggang Deng, Hongchang Ma, Peifu Feng, Jing Liu, Weihong Tan, Mao Ye
WD repeat protein 79 (WDR79) is a member of the WD-repeat protein family and functions as a scaffold protein during telomerase assembly, Cajal body formation and DNA double strand break repair. We have previously shown that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer (NSCLC) and it accelerates cell proliferation in NSCLC. However, the detailed mechanism underlying the role of WDR79 in the proliferation of NSCLC cells remains unclear. Here, we report the discovery of a molecular interaction between WDR79 and USP7 and show its functional significance in linking the Mdm2-p53 pathway to the proliferation of NSCLC cells...
April 13, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28400564/a-novel-4-arm-dna-rna-nanoconstruct-triggering-rapid-apoptosis-of-triple-negative-breast-cancer-cells-within-24%C3%A2-hours
#8
Joline Tung, Lih Shin Tew, Yuan-Man Hsu, Yit Lung Khung
Measuring at ~30 nm, a fully customizable holliday junction DNA nanoconstruct, was designed to simultaneously carry three unmodified SiRNA strands for apoptosis gene knockout in cancer cells without any assistance from commercial transfection kits. In brief, a holliday junction structure was intelligently designed to present one arm with a cell targeting aptamer (AS1411) while the remaining three arms to carry different SiRNA strands by means of DNA/RNA duplex for inducing apoptosis in cancer cells. By carrying the three SiRNA strands (AKT, MDM2 and Survivin) into triple negative breast MDA-MB-231 cancer cells, cell number had reduced by up to ~82% within 24 hours solely from one single administration of 32 picomoles...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28400230/investigation-of-the-inhibitory-mechanism-of-apomorphine-against-mdm2-p53-interaction
#9
Hiroyuki Ishiba, Taro Noguchi, Keitou Shu, Hiroaki Ohno, Kaori Honda, Yasumitsu Kondoh, Hiroyuki Osada, Nobutaka Fujii, Shinya Oishi
Mirror-image screening using d-proteins is a powerful approach to provide mirror-image structures of chiral natural products for drug screening. During the course of our screening study for novel MDM2-p53 interaction inhibitors, we identified that NPD6878 (R-(-)-apomorphine) inhibited both the native l-MDM2-l-p53 interaction and the mirror-image d-MDM2-d-p53 interaction at equipotent doses. In addition, both enantiomers of apomorphine showed potent inhibitory activity against the native MDM2-p53 interaction...
March 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28394340/selective-targeting-p53-wt-lung-cancer-cells-harboring-homozygous-p53-arg72-by-an-inhibitor-of-cypa
#10
W Lu, F Cheng, W Yan, X Li, X Yao, W Song, M Liu, X Shen, H Jiang, J Chen, J Li, J Huang
TP53 plays essential roles in tumor initiation and progression, and is frequently mutated in cancer. However, pharmacological stabilization and reactivation of p53 have not been actively explored for targeted cancer therapies. Herein, we identify a novel Cyclophilin A (CypA) small molecule inhibitor (HL001) that induces non-small cell lung cancer (NSCLC) cell cycle arrest and apoptosis via restoring p53 expression. We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination. Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of reactive oxygen species and DNA damage by HL001 contribute to p53 stabilization...
April 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28393453/novel-mechanism-of-mirna-365-regulated-trophoblast-apoptosis-in-recurrent-miscarriage
#11
Wei Zhao, Wei-Wei Shen, Xiao-Mei Cao, Wen-Yan Ding, Lin-Ping Yan, Ling-Juan Gao, Xiu-Ling Li, Tian-Ying Zhong
Clinical pregnancies increasingly end in recurrent miscarriage (RM) during the first trimester, with genetic factors shouldering the main responsibility. MicroRNAs (miRNAs) regulate gene expression in a wide array of important biological processes. We examined the potential role of dysregulated miRNAs in RM pathogenesis and trophoblast development as an approach to elucidate the molecular mechanism behind RM. miRNA profiles from clinical specimens of RM and induced abortion (IA) were compared, and several miRNAs were found to be aberrantly expressed in RM samples...
April 10, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28388005/a-novel-methodology-for-the-incorporation-of-chiral-linkers-in-stapled-peptides
#12
Juan C Serrano, James Sipthorp, Wenshu Xu, Laura S Itzhaki, Steven V Ley
Stapled peptides have arisen as a new class of chemical probe and potential therapeutic agents to modulate protein-protein interactions. Here, we report the first two-component i,i+7 stapling methodology using two orthogonal, on-resin stapling reactions to incorporate linkers bearing a chiral center on a p53-derived stapled peptide. Post-stapling modifications to the staple chain were performed on-resin, enabling rapid access to various peptide derivatives from a single staple. The stapled peptides have increased helicity, protease stability and in vitro binding affinities to MDM2 compared to the unstapled peptide...
April 7, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28387973/fusaric-acid-induces-dna-damage-and-post-translational-modifications-of-p53-in-human-hepatocellular-carcinoma-hepg2-cells
#13
Terisha Ghazi, Savania Nagiah, Charlette Tiloke, Naeem Sheik Abdul, Anil A Chuturgoon
Fusaric acid (FA), a common fungal contaminant of maize, is known to mediate toxicity in plants and animals; however, its mechanism of action is unclear. p53 is a tumour suppressor protein that is activated in response to cellular stress. The function of p53 is regulated by post-translational modifications - ubiquitination, phosphorylation and acetylation. This study investigated a possible mechanism of FA induced toxicity in the human hepatocellular carcinoma (HepG2 ) cell line. The effect of FA on DNA integrity and post-translational modifications of p53 were investigated...
April 7, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28376372/synthesis-of-xanthone-derivatives-and-studies-on-the-inhibition-against-cancer-cells-growth-and-synergistic-combinations-of-them
#14
Jie Liu, Jianrun Zhang, Huailing Wang, Zhijun Liu, Cao Zhang, Zhenlei Jiang, Heru Chen
34 Xanthones were synthesized by microwave assisted technique. Their in vitro inhibition activities against five cell lines growth were evaluated. The SAR has been thoroughly discussed. 7-Bromo-1,3-dihydroxy-9H-xanthen-9-one (3-1) was confirmed as the most active agent against MDA-MB-231 cell line growth with an IC50 of 0.46 ± 0.03 μM. Combination of 3-1 and 5,6-dimethylxanthone-4-acetic acid (DMXAA) showed the best synergistic effect. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for both monomers and the combination...
March 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28376214/prospective-validation-of-diagnostic-tumor-biomarkers-in-men-treated-with-radiotherapy-for-prostate-cancer
#15
Alan Pollack, Deukwoo Kwon, Gail Walker, Li Yan Khor, Eric M Horwitz, Mark K Buyyounouski, Radka Stoyanova
Background: In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial. Methods: Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation...
February 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28374118/structural-insight-into-the-mechanism-of-dibenzo-a-l-pyrene-and-benzo-a-pyrene-mediated-cell-proliferation-using-molecular-docking-simulations
#16
M Kalim A Khan, Salman Akhtar, Jamal M Arif
In the proposed work, we have explicated the mechanism of dibenzo[a,l]pyrene (DBP) and benzo[a]pyrene (BP) modulated cell proliferation by assessing the plausible binding with CASPASES, BAX, Bcl-2, MDM2, p53, p21, p16, CylinD1-CDK4 complex, CylinE1-CDK2 complex, H-Ras, K-Ras, BRCA1, and BRCA2 through exploiting the inherent potential of AutoDock Tools 4.0. In silico findings revealed that potent carcinogenic metabolites of DBP (e.g., (-)-anti-DBPDE and (+)-syn-DBPDE) and BP (e.g., (+)-anti-BPDE) exhibited better binding interactions to Caspase-9 than Caspase-8 and Caspase-3...
April 3, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/28369097/p53-pathway-determines-the-cellular-response-to-alcohol-induced-dna-damage-in-mcf-7-breast-cancer-cells
#17
Ming Zhao, Erin W Howard, Zhiying Guo, Amanda B Parris, Xiaohe Yang
Alcohol consumption is associated with increased breast cancer risk; however, the underlying mechanisms that contribute to mammary tumor initiation and progression are unclear. Alcohol is known to induce oxidative stress and DNA damage; likewise, p53 is a critical modulator of the DNA repair pathway and ensures genomic integrity. p53 mutations are frequently detected in breast and other tumors. The impact of alcohol on p53 is recognized, yet the role of p53 in alcohol-induced mammary carcinogenesis remains poorly defined...
2017: PloS One
https://www.readbyqxmd.com/read/28366825/novel-quinuclidinone-derivatives-induced-apoptosis-in-human-breast-cancer-via-targeting-p53
#18
Ahmed Malki, Rasha Y Elbayaa, Omnia Ali, Ahmed Sultan, Amal M Youssef
Small molecules that can target human cancers have been highly sought to increase the anticancer efficacy, the present work describes the design and synthesis of novel series of five quinuclidinone derivatives (2a-2e). Their anticancer activities were investigated against breast cancer cells MCF-7, MDA-MB-231 breast cancer cells harboring mutant p53 and normal breast counterpart MCF-12a. Derivative 2e reduced proliferation of MCF-7 and MCF-12a while it has no effect on MDA-MB-231. Derivative 2e induced apoptosis in MCF-7 cells which is further confirmed by TUNEL assay and it reduced the percentage of cell in G2/M phase as confirmed by increased expression of cyclin B and reduced expression of cyclin D1...
March 22, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28349922/coumarin-chalcone-hybrid-instigates-dna-damage-by-minor-groove-binding-and-stabilizes-p53-through-post-translational-modifications
#19
Raghib Ashraf, Hamidullah, Mohammad Hasanain, Praveen Pandey, Mayank Maheshwari, L Ravithej Singh, M Quadir Siddiqui, Rituraj Konwar, Koneni V Sashidhara, Jayanta Sarkar
S009-131, a coumarin-chalcone hybrid, had been shown to possess anti-proliferative and anti-tumour effect by triggering apoptosis. In this report, we investigated role of DNA damage signalling pathway in S009-131 induced cancer cell death. Here we show that S009-131 causes DNA damage by potential binding to the minor groove which led to the phosphorylation and activation of ATM and DNA-PK, but not ATR, at earlier time points in order to initiate repair process. S009-131 induced DNA damage response triggered activation of p53 through phosphorylation at its key residues...
March 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28341911/nutlin-3-an-antagonist-of-mdm2-enhances-the-radiosensitivity-of-esophageal-squamous-cancer-with-wild-type-p53
#20
Tianli He, Jiayou Guo, Hongmei Song, Hongcheng Zhu, Xiaoke Di, Hua Min, Yuandong Wang, Guangzong Chen, Wangshu Dai, Jianhua Ma, Xinchen Sun, Jianxin Ma
Murine double minute 2 (MDM2) negatively regulates the activity of the p53 protein and plays a vital role in cell cycle arrest, apoptosis, and senescence mediated by p53. Nutlin-3, an antagonist of MDM2, is frequently used in anti-cancer studies. In many human tumors, nutlin-3 stabilizes p53 status and enhances p53 expression in cells with wild-type p53. However, the effect of nutlin-3 combined with radiotherapy on esophageal squamous cancer (ESCC) has not been reported. In this study, we examined whether nutlin-3 increases the radiosensitivity of ESCC in vitro and in vivo...
March 24, 2017: Pathology Oncology Research: POR
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