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https://www.readbyqxmd.com/read/28441761/e2-er-%C3%AE-enhances-calcineurin-protein-degradation-and-pi3k-akt-mdm2-signal-transduction-to-inhibit-iso-induced-myocardial-cell-apoptosis
#1
Kuan-Ho Lin, Wei-Wen Kuo, Marthandam Asokan Shibu, Cecilia-Hsuan Day, You-Liang Hsieh, Li-Chin Chung, Ray-Jade Chen, Su-Ying Wen, Vijaya Padma Viswanadha, Chih-Yang Huang
Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2), for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs). In addition, protein phosphatase such as protein phosphatase 1 (PP1) and calcineurin (PP2B) are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation...
April 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28441013/cytotoxicity-of-pyrazine-based-cyclometalated-c-n-pz-c-au-iii-carbene-complexes-impact-of-the-nature-of-the-ancillary-ligand-on-the-biological-properties
#2
Benoît Bertrand, Julio Fernandez-Cestau, Jesus Angulo, Marco M D Cominetti, Zoë A E Waller, Mark Searcey, Maria A O'Connell, Manfred Bochmann
The synthesis of a series of cyclometalated gold(III) complexes supported by pyrazine-based (C^N^C)-type pincer ligands is reported, including the crystal structure of a cationic example. The compounds provide a new platform for the study of antiproliferative properties of gold(III) complexes. Seven complexes were tested: the neutral series (C^N(pz)^C)AuX [X = Cl (1), 6-thioguanine (4), C≡CPh (5), SPh (6)] and an ionic series that included the N-methyl complex [(C^N(pzMe)^C)AuCl]BF4 (7) and the N-heterocyclic carbene complexes [(C^N(pz)^C)AuL](+) with L = 1,3-dimethylbenzimidazol-2-ylidene (2) or 1,3,7,9-tetramethylxanthin-8-ylidene (3)...
April 25, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28440085/actinomycin-d-synergistically-enhances-the-cytotoxicity-of-cddp-on-kb-cells-by-activating-p53-via-decreasing-p53-mdm2-complex
#3
Lin Wang, Xiao-Cong Pang, Zi-Ru Yu, Sheng-Qian Yang, Ai-Lin Liu, Jin-Hua Wang, Guan-Hua Du
The aim of this study is to investigate the synergism of low dose of actinomycin D (LDActD) to the cytotoxicity of cisplatin (CDDP) on KB cells. The role of P53 reactivation by LDActD in the synergism and its mechanism were further studied. Cell viability was determined by MTT assay. Apoptosis was determined by AnnexinV-FITC/PI staining. Mitochondrial membrane potential (MMP) was detected by JC-1 staining. Expression of proteins was detected by Western blotting (WB) and/or immunofluorescence (IF). Molecular docking of actinomycin D (ACTD) to Mouse double minute 2 homolog (MDM2) and Mouse double minute 2 homolog X (MDMX)...
April 25, 2017: Journal of Asian Natural Products Research
https://www.readbyqxmd.com/read/28438863/the-role-of-p16-and-mdm2-gene-polymorphisms-in-prolactinoma-mdm2-gene-polymorphisms-may-be-associated-with-tumor-shrinkage
#4
Seda Turgut, Muzaffer Ilhan, Saime Turan, Ozcan Karaman, Ilhan Yaylim, Ozlem Kucukhuseyin, Ertugrul Tasan
AIM: Prolactinomas are thought to arise from clonal expansion of a single mutated cell which is subjected to growth stimuli of several permissive factors, although the pathogenetic mechanisms underlying tumorigenesis remain unclear. The present study aimed to investigate the role of p16 (540C→G and 580C→T) and mouse double minute 2 (MDM2) (SNP309T→G) gene polymorphisms in tumorigenesis and characteristics of prolactinoma. PATIENTS AND METHODS: A total of 74 patients with prolactinoma and 100 age- and gender-matched healthy individuals were enrolled in the study...
May 2017: In Vivo
https://www.readbyqxmd.com/read/28436570/bre-enhances-osteoblastic-differentiation-by-promoting-the-mdm2-mediated-degradation-of-p53
#5
Fujun Jin, Yiliang Wang, Xiaojing Wang, Yanting Wu, Xiaoyan Wang, Qiuying Liu, Yexuan Zhu, Enqi Liu, Jianglin Fan, Yifei Wang
Bre is a conserved cellular protein expressed in various tissues. Its major function includes DNA damage repair and anti-apoptosis. Recent studies indicate that Bre is potentially involved in stem cell differentiation although pathophysiological significance along with the molecular mechanisms is still unclear. Here, we report that Bre protein was substantially expressed in the bone tissue and its expression was highly upregulated during the osteogenic differentiation. To test a hypothesis that Bre plays functional roles in the process of osteogenic differentiation, we examined the expression of Bre in an osteoporosis mouse model...
April 24, 2017: Stem Cells
https://www.readbyqxmd.com/read/28427187/rita-displays-anti-tumor-activity-in-medulloblastomas-independent-of-tp53-status
#6
Aline Gottlieb, Kristina Althoff, Laura Grunewald, Theresa Thor, Andrea Odersky, Marc Schulte, Hedwig E Deubzer, Lukas Heukamp, Angelika Eggert, Alexander Schramm, Johannes H Schulte, Annette Künkele
Current therapy of medulloblastoma, the most common malignant brain tumor of childhood, achieves 40-70% survival. Secondary chemotherapy resistance contributes to treatment failure, where TP53 pathway dysfunction plays a key role. MDM2 interaction with TP53 leads to its degradation. Reactivating TP53 functionality using small-molecule inhibitors, such as RITA, to disrupt TP53-MDM2 binding may have therapeutic potential. We show here that RITA decreased viability of all 4 analyzed medulloblastoma cell lines, regardless of TP53 functional status...
March 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28425916/combined-alk-and-mdm2-inhibition-increases-antitumor-activity-and-overcomes-resistance-in-human-alk-mutant-neuroblastoma-cell-lines-and-xenograft-models
#7
Hui Qin Wang, Ensar Halilovic, Xiaoyan Li, Jinsheng Liang, Yichen Cao, Daniel P Rakiec, David A Ruddy, Sebastien Jeay, Jens U Wuerthner, Noelito Timple, Shailaja Kasibhatla, Nanxin Li, Juliet A Williams, William R Sellers, Alan Huang, Fang Li
The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells...
April 20, 2017: ELife
https://www.readbyqxmd.com/read/28425639/designing-dual-inhibitors-of-mdm2-mdmx-unexpected-coupling-of-water-with-gatekeeper-y100-99
#8
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/28424409/clinical-genomic-profiling-to-identify-actionable-alterations-for-investigational-therapies-in-patients-with-diverse-sarcomas
#9
Roman Groisberg, David S Hong, Vijaykumar Holla, Filip Janku, Sarina Piha-Paul, Vinod Ravi, Robert Benjamin, Shreyas Kumar Patel, Neeta Somaiah, Anthony Conley, Siraj M Ali, Alexa B Schrock, Jeffrey S Ross, Philip J Stephens, Vincent A Miller, Shiraj Sen, Cynthia Herzog, Funda Meric-Bernstam, Vivek Subbiah
BACKGROUND: There are currently no United States Food and Drug Administration approved molecularly matched therapies for sarcomas except gastrointestinal stromal tumors. Complicating this is the extreme diversity, heterogeneity, and rarity of these neoplasms. Few therapeutic options exist for relapsed and refractory sarcomas. In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy. However, a systematic analysis of actionable mutations has yet to be completed...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418896/nfkb-is-essential-for-activin-induced-colorectal-cancer-migration-via-upregulation-of-pi3k-mdm2-pathway
#10
Arundhati Jana, Nancy L Krett, Grace Guzman, Ahmer Khalid, Ozkan Ozden, Jonas J Staudacher, Jessica Bauer, Seung Hyun Baik, Timothy Carroll, Cemal Yazici, Barbara Jung
Colorectal cancer (CRC) remains a common and deadly cancer due to metastatic disease. Activin and TGFB (TGFβ) signaling are growth suppressive pathways that exert non-canonical pro-metastatic effects late in CRC carcinogenesis. We have recently shown that activin downregulates p21 via ubiquitination and degradation associated with enhanced cellular migration independent of SMADs. To investigate the mechanism of metastatic activin signaling, we examined activated NFkB signaling and activin ligand expression in CRC patient samples and found a strong correlation...
March 18, 2017: Oncotarget
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
#11
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/28415661/specific-amplifications-and-copy-number-decreases-during-human-neural-stem-cells-differentiation-towards-astrocytes-neurons-and-oligodendrocytes
#12
Ulrike Fischer, Ella Kim, Andreas Keller, Eckart Meese
There is growing evidence that gene amplifications are an attribute of normal cells during development and differentiation. During neural progenitor cell differentiation half of the genome is involved in amplification process. To answer the question how specific amplifications occur at different stages and in different lineages of differentiation we analyzed the genes CDK4, MDM2, EGFR, GINS2, GFAP, TP53, DDB1 and MDM4 in human neural stem cells that were induced to differentiate towards astrocytes, neurons and oligodendrocytes...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414026/targeting-oct2-and-p53-formononetin-prevents-cisplatin-induced-acute-kidney-injury
#13
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
#14
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
#15
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
#16
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
#17
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/28404975/mdm2-antagonists-synergize-with-pi3k-mtor-inhibition-in-well-differentiated-dedifferentiated-liposarcomas
#18
Audrey Laroche, Vanessa Chaire, Marie-Paule Algeo, Marie Karanian, Benjamin Fourneaux, Antoine Italiano
BACKGROUND: Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) are characterized by a consistent amplification of the MDM2 gene. The PI3K/AKT/mTOR pathway has been suggested to play also an important role in their tumorigenesis. Our goal was to determine whether combined MDM2 and PI3K/AKT/mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS. METHODS: WDLPS/DDLPS cells were exposed to RG7388 (MDM2 antagonist) and BEZ235 (PI3K/mTOR dual inhibitor) after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis...
March 17, 2017: Oncotarget
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
#19
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
#20
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
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