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Jinhua Jiang, Yan Shi, Ruixian Yu, Liping Chen, Xueping Zhao
Azoxystrobin (AZ) is a broad-spectrum systemic fungicide that widely used in the world. The present study investigated the toxicity effects on zebrafish after short-term exposure of AZ. Results demonstrated that the larval stage was most susceptible to AZ in the multiple life stages of zebrafish, with 96 h-LC50 value of 0.777 mg/L. Zebrafish larvae were exposed to different AZ concentrations (0, 0.1, 1, 10, 100 μg/L) and examined on 24, 48 and 72 h. It was found that AZ induced ROS accumulation, increased GST, GPX and POD activity and the transcriptions of antioxidant and stress response related genes, while the opposite trend occurred for SOD and CAT activity in 24-h or 48-h exposure period...
March 8, 2018: Chemosphere
Chen Katz, Ana Maria Low-Calle, Joshua Choe, Oleg Laptenko, David Tong, Jazmine-Saskya N Joseph-Chowdhury, Francesca Garofalo, Yan Zhu, Assaf Friedler, Carol Prives
The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro...
March 16, 2018: Genes & Development
Ziling Fang, Bo Cao, Jun-Ming Liao, Jun Deng, Kevin D Plummer, Peng Liao, Tao Liu, Wensheng Zhang, Kun Zhang, Li Li, David Margolin, Shelya X Zeng, Jianping Xiong, Hua Lu
Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity towards p53...
March 16, 2018: ELife
Colin R O'Dowd, Matthew D Helm, J S Shane Rountree, Jakub T Flasz, Elias Arkoudis, Hugues Miel, Peter R Hewitt, Linda Jordan, Oliver Barker, Caroline Hughes, Ewelina Rozycka, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Stephanie Feutren-Burton, Scarlett Dvorkin, Gerald Gavory, Timothy Harrison
Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography...
March 8, 2018: ACS Medicinal Chemistry Letters
Gamze Kuser-Abali, Lu Gong, Jiawei Yan, Qingqing Liu, Weiqi Zeng, Amanda Williamson, Chuan Bian Lim, Mary Ellen Molloy, John B Little, Lei Huang, Zhi-Min Yuan
Renewable tissues exhibit heightened sensitivity to DNA damage, which is thought to result from a high level of p53. However, cell proliferation in renewable tissues requires p53 down-regulation, creating an apparent discrepancy between the p53 level and elevated sensitivity to DNA damage. Using a combination of genetic mouse models and pharmacologic inhibitors, we demonstrate that it is p53-regulated MDM2 that functions together with MDMX to regulate DNA damage sensitivity by targeting EZH2 (enhancer of zeste homolog 2) for ubiquitination/degradation...
March 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Zihao Chen, Hongping Ju, Shan Yu, Ting Zhao, Xiaojie Jing, Ping Li, Jing Jia, Nan Li, Bibo Tan, Yong Li
Gastric cancer (GC) is one of a major global health problem especially in Asia. Nowadays, long non-coding RNA has gained significantly attention in the current research climate such as carcinogenesis. This research desired to explore the mechanism of Prader-Willi region non-protein coding RNA 1 (PWRN1) on regulating GC process. Differentially expressed lncRNAs in GC tissues were screened out through microarray analysis. The RNA and protein expression level was detected by qRT-PCR and western blot. Cell proliferation, apoptosis rate, metastasis abilities were respectively determined by CCK8, flow cytometry, wound healing and transwell assay...
March 13, 2018: Clinical Science (1979-)
Brent E Fitzwalter, Christina G Towers, Kelly D Sullivan, Zdenek Andrysik, Maria Hoh, Michael Ludwig, Jim O'Prey, Kevin M Ryan, Joaquin M Espinosa, Michael J Morgan, Andrew Thorburn
Macroautophagy (autophagy) is intimately linked with cell death and allows cells to evade apoptosis. This has prompted clinical trials to combine autophagy inhibitors with other drugs with the aim of increasing the likelihood of cancer cells dying. However, the molecular basis for such effects is unknown. Here, we describe a transcriptional mechanism that connects autophagy to apoptosis. The autophagy-regulating transcription factor, FOXO3a, is itself turned over by basal autophagy creating a potential feedback loop...
March 12, 2018: Developmental Cell
Wen Hui, Shenghua Liu, Jie Zheng, Zujun Fang, Qiang Ding, Chenchen Feng
Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In-silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin-3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation...
March 13, 2018: Cancer Medicine
Elena Maryamchik, Kirill A Lyapichev, Bradford Halliday, Andrew E Rosenberg
We report a first case of paraneoplastic human chorionic gonadotropin (HCG) production in a dedifferentiated liposarcoma with rhabdosarcomatous differentiation in an 83-year-old man with a retroperitoneal mass, unilateral scrotal enlargement, and a serum HCG level of 843 IU/L. Core biopsy of the retroperitoneal mass revealed rhabdomyosarcoma. Orchiectomy revealed a paratesticular dedifferentiated liposarcoma with rhabdosarcomatous differentiation. Fluorescence in situ hybridization analysis performed on both the retroperitoneal and paratesticular masses revealed amplification of MDM2...
March 1, 2018: International Journal of Surgical Pathology
Helena Yu, Ken Suzawa, Emmet J Jordan, Ahmet Zehir, Andy Ni, Hyunjae Ryan Kim, Mark G Kris, Matthew D Hellmann, Bob T Li, Romel Somwar, David B Solit, Michael F Berger, Maria E Arcila, Gregory J Riely, Marc Ladanyi
PURPOSE: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data...
March 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Diana M Mitrea, Richard W Kriwacki
Arf levels are tightly regulated in cells and correlate with the level of ribosome biogenesis and proliferative status of cells. Through multivalent interactions with NPM1 - a regulator of ribosome biogenesis, and Mdm2 - a regulator of cellular fate, Arf integrates within the nucleolar matrix, altering its structure, dynamics and function and therefore modulates the cell cycle.
March 2018: FEBS Journal
Sofia Ferreira-Gonzalez, Wei-Yu Lu, Alexander Raven, Benjamin Dwyer, Tak Yung Man, Eoghan O'Duibhir, Philip J Starkey Lewis, Lara Campana, Tim J Kendall, Thomas G Bird, Nuria Tarrats, Juan-Carlos Acosta, Luke Boulter, Stuart J Forbes
Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes...
March 9, 2018: Nature Communications
Dawei Li, Omid Tavana, Shao-Cong Sun, Wei Gu
Mdm2 and Mdmx, both major repressors of p53 in human cancers, are predominantly localized to the nucleus and cytoplasm, respectively. The mechanism by which subcellular localization of Mdmx is regulated remains unclear. In this study, we identify the E3 ligase Peli1 as a major binding partner and regulator of Mdmx in human cells. Peli1 bound Mdmx in vitro and in vivo and promoted high levels of ubiquitination of Mdmx. Peli1-mediated ubiquitination was degradation-independent, promoting cytoplasmic localization of Mdmx which in turn resulted in p53 activation...
March 9, 2018: Cancer Research
Fabian Paul, Frank Noé, Thomas R Weikl
Unstructured protein and peptides typically fold during binding to ligand proteins. A challenging problem is to identify the mechanism and kinetics of these binding-induced folding processes in experiments and atomistic simulations. In this article, we present a detailed picture for the folding of the inhibitor peptide PMI into a helix during binding to the oncoprotein fragment25-109 Mdm2 obtained from atomistic, explicit-water simulations and Markov state modeling. We find that binding-induced folding of PMI is highly parallel and can occur along a multitude of pathways...
March 9, 2018: Journal of Physical Chemistry. B
Mohammed Benadallah, Oualid Talhi, Fatiha Nouali, Nourredine Choukchou-Braham, Khaldoun Bachari, Artur M S Silva
The present review deals with the progress in medicinal chemistry of spirocyclic compounds, a wider class of natural and synthetic organic molecules, defined as a hybrid of two molecular entities covalently linked via a unique tetrahedral carbon. This spiro central carbon confers to the molecules a tridimensional structurally oriented framework, which is found in many medicinally relevant compounds, a well-known example is the anti-hypertensive spironolactone. Various bioactive natural products possess the privileged spiro linkage and different chemo-types thereof become synthetically accessible since the 20th century...
March 9, 2018: Current Medicinal Chemistry
Rosa Mistica C Ignacio, Yuan-Lin Dong, Syeda M Kabir, Hyeongjwa Choi, Eun-Sook Lee, Andrew J Wilson, Alicia Beeghly-Fadiel, Margaret M Whalen, Deok-Soo Son
Ovarian cancer (OC) has the highest rate of mortality among gynecological malignancy. Chemokine receptor CXCR2 in OC is associated with poor outcomes. However, the mechanisms by which CXCR2 regulates OC proliferation remain poorly understood. We generated CXCR2-positive cells from parental p53 wild-type (WT), mutant and null OC cells, and assessed the roles of CXCR2 on proliferation of OC cells in p53-dependent and independent manner. CXCR2 promoted cell growth rate: p53WT > mutant = null cells. Nutlin-3, a p53 stabilizer, inhibited cell proliferation in p53WT cells, but had little effect in p53-mutant or null cells, indicating p53-dependence of CXCR2-mediated proliferation...
February 9, 2018: Oncotarget
Leomar Y Ballester, Zain Boghani, David S Baskin, Gavin W Britz, Randall Olsen, Gregory N Fuller, Suzanne Z Powell, Matthew D Cykowski
Astrocytes with multiple micronuclei ("Creutzfeldt cells") in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high-grade glioma versus tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood...
March 6, 2018: Brain Pathology
Jo Ishizawa, Kenji Nakamaru, Takahiko Seki, Koichi Tazaki, Kensuke Kojima, Dhruv Chachad, Ran Zhao, Lauren E Heese, Wencai Ma, Man Chun John Ma, Courtney D DiNardo, Sherry A Pierce, Keyur P Patel, Archie Tse, R Eric Davis, Arvind Rao, Michael Andreeff
Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells, however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b...
February 28, 2018: Cancer Research
Naohiro Makise, Masaya Sekimizu, Takashi Kubo, Susumu Wakai, Shun-Ichi Watanabe, Tomoyasu Kato, Takayuki Kinoshita, Nobuyoshi Hiraoka, Masashi Fukayama, Akira Kawai, Hitoshi Ichikawa, Akihiko Yoshida
AIMS: Extraskeletal osteosarcoma (ESOS) is a sarcoma in the non-skeletal tissue that directly produces neoplastic osteoid or bone. Dedifferentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumor (MPNST) are the two most common types of sarcoma that can harbor heterologous osteosarcomatous differentiation. We aimed to determine the potential relationship of ESOS to DDLPS and MPNST. METHODS AND RESULTS: We investigated MDM2 and H3K27me3 status in 19 cases of ESOS, 2 of which contained a low-grade component...
February 28, 2018: Histopathology
Andrés Pizzorno, Julia Dubois, Daniela Machado, Gaëlle Cartet, Aurelien Traversier, Thomas Julien, Bruno Lina, Jean-Christophe Bourdon, Manuel Rosa-Calatrava, Olivier Terrier
The interplay between influenza A viruses (IAV) and the p53 pathway has been reported in several studies, highlighting the antiviral contribution of p53. Here, we investigated the impact of IAV on the E3-ubiquitin ligase Mdm2, a major regulator of p53, and observed that IAV targets Mdm2, notably via its non-structural protein (NS1), therefore altering Mdm2 stability, p53/Mdm2 interaction and regulatory loop during the time-course of infection. This study also highlights a new antiviral facet of Mdm2 possibly increasing the list of its many p53-independent functions...
February 27, 2018: Scientific Reports
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