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https://www.readbyqxmd.com/read/28032595/prospective-identification-of-resistance-mechanisms-to-hsp90-inhibition-in-kras-mutant-cancer-cells
#1
Arefeh Rouhi, Christina Miller, Sarah Grasedieck, Stefanie Reinhart, Britta Stolze, Hartmut Döhner, Florian Kuchenbauer, Lars Bullinger, Stefan Fröhling, Claudia Scholl
Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71...
December 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27997009/-genomics-of-lung-adenocarcinoma-pathogenetic-significance-and-clinical-applications
#2
Raffaele Palmirotta, Silvana Acquafredda, Antonella Argentiero, Claudia Carella, Laura Lanotte, Nicla Pappagallo, Davide Quaresmini, Franco Silvestris
Diagnostic and therapeutic approaches to non small cell lung cancer (NSCLC), especially adenocarcinoma, have recently undergone dramatic evolution according to the tremendous amount of molecular data collected on this cancer. In fact, the application of oncogenomics has identified novel molecular subtypes of NSCLC and led the way to diagnostic criteria based on the expression of specific genetic alterations that can provide prognostic and specific indications to the molecular targeted therapies. In NSCLC, several genes show "driver" molecular alterations that confer oncogenic potential to progenitor cells through the enrollment of metabolic pathways critical for cell proliferation and tumor development...
December 2016: Recenti Progressi in Medicina
https://www.readbyqxmd.com/read/27987076/hop-expression-is-regulated-by-p53-and-ras-and-characteristic-of-a-cancer-gene-signature
#3
Stacey A Mattison, Gregory L Blatch, Adrienne L Edkins
The Hsp70/Hsp90 organising protein (HOP) is a co-chaperone essential for client protein transfer from Hsp70 to Hsp90 within the Hsp90 chaperone machine. Although HOP is upregulated in various cancers, there is limited information from in vitro studies on how HOP expression is regulated in cancer. The main objective of this study was to identify the HOP promoter and investigate its activity in cancerous cells. Bioinformatic analysis of the -2500 to +16 bp region of the HOP gene identified a large CpG island and a range of putative cis-elements...
December 16, 2016: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/27966599/transcriptional-analysis-of-degenerate-strain-clostridium-beijerinckii-dg-8052-reveals-a-pleiotropic-response-to-caco3-associated-recovery-of-solvent-production
#4
Shengyin Jiao, Yan Zhang, Caixia Wan, Jia Lv, Renjia Du, Ruijuan Zhang, Bei Han
Degenerate Clostridium beijerinckii strain (DG-8052) can be partially recovered by supplementing CaCO3 to fermentation media. Genome resequencing of DG-8052 showed no general regulator mutated. This study focused on transcriptional analysis of DG-8052 and its response to CaCO3 treatment via microarray. The expressions of 5168 genes capturing 98.6% of C. beijerinckii NCIMB 8052 genome were examed. The results revealed that with addition of CaCO3 565 and 916 genes were significantly up-regulated, and 704 and 1044 genes significantly down-regulated at acidogenic and solventogenic phase of DG-8052, respectively...
December 14, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27959342/ailanthone-targets-p23-to-overcome-mdv3100-resistance-in-castration-resistant-prostate-cancer
#5
Yundong He, Shihong Peng, Jinhua Wang, Huang Chen, Xiaonan Cong, Ang Chen, Meichun Hu, Min Qin, Haigang Wu, Shuman Gao, Liguo Wang, Xin Wang, Zhengfang Yi, Mingyao Liu
Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours...
December 13, 2016: Nature Communications
https://www.readbyqxmd.com/read/27906968/structural-and-functional-recovery-of-sensory-cilia-in-c-elegans-ift-mutants-upon-aging
#6
Astrid Cornils, Ashish K Maurya, Lauren Tereshko, Julie Kennedy, Andrea G Brear, Veena Prahlad, Oliver E Blacque, Piali Sengupta
The majority of cilia are formed and maintained by the highly conserved process of intraflagellar transport (IFT). Mutations in IFT genes lead to ciliary structural defects and systemic disorders termed ciliopathies. Here we show that the severely truncated sensory cilia of hypomorphic IFT mutants in C. elegans transiently elongate during a discrete period of adult aging leading to markedly improved sensory behaviors. Age-dependent restoration of cilia morphology occurs in structurally diverse cilia types and requires IFT...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27888470/mutation-of-the-ser18-phosphorylation-site-on-the-sole-saccharomyces-cerevisiae-ucs-protein-she4-can-compromise-high-temperature-survival
#7
Susana Gomez-Escalante, Peter W Piper, Stefan H Millson
Folding of the myosin head often requires the joint actions of Hsp90 and a dedicated UNC45, Cro1, She4 (UCS) domain-containing cochaperone protein. Relatively weak sequence conservation exists between the single UCS protein of simple eukaryotes (She4 in budding yeast) and the two UCS proteins of higher organisms (the general cell and smooth muscle UNC45s; UNC45-GC and UNC45-SM respectively). In vertebrates, UNC45-GC facilitates cytoskeletal function whereas the 55% identical UNC45-SM assists in the assembly of the contractile apparatus of cardiac and skeletal muscles...
November 25, 2016: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/27864516/on-the-un-predictability-of-a-large-intragenic-fitness-landscape
#8
Claudia Bank, Sebastian Matuszewski, Ryan T Hietpas, Jeffrey D Jensen
The study of fitness landscapes, which aims at mapping genotypes to fitness, is receiving ever-increasing attention. Novel experimental approaches combined with next-generation sequencing (NGS) methods enable accurate and extensive studies of the fitness effects of mutations, allowing us to test theoretical predictions and improve our understanding of the shape of the true underlying fitness landscape and its implications for the predictability and repeatability of evolution. Here, we present a uniquely large multiallelic fitness landscape comprising 640 engineered mutants that represent all possible combinations of 13 amino acid-changing mutations at 6 sites in the heat-shock protein Hsp90 in Saccharomyces cerevisiae under elevated salinity...
December 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27846719/-impact-of-hsp90-inhibition-on-viability-and-cell-cycle-in-relation-to-p53-status
#9
M Pastorek, P Müller, B Vojtěšek
BACKGROUND: Chaperone system inhibition is a recent promising strategy for cancer treatment that exploits increased metabolic needs required for rapid proliferation as well as higher level of proteotoxic stress in neoplastic cells. Chaperone HSP90 plays a key role in proper folding of many de novo synthesized proteins, so-called clients, including tumor suppressor p53 which is commonly mutated in majority of cancers. Aim of this work was therefore to understand the impact of HSP90 inhibition by NVP-AUY922 on breast cancer cell lines with wild-type and mutated p53...
2016: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/27845047/tuberous-sclerosis-complex-protein-1-expression-is-affected-by-vhl-gene-alterations-and-hif-1%C3%AE-production-in-sporadic-clear-cell-renal-cell-carcinoma
#10
Svetozar S Damjanovic, Bojana B Ilic, Bojana B Beleslin Cokic, Jadranka A Antic, Jovana Z Bankovic, Ivana T Milicevic, Gordana S Rodic, Dusan S Ilic, Vera N Todorovic, Nela Puskas, Cane D Tulic
Alterations in von Hippel-Lindau gene (VHL) do not determine deregulation of hypoxia-inducible factors (HIFs) in clear-cell renal carcinoma (ccRCC). Their effects on tuberous sclerosis proteins (TSC1/2) and heat shock protein 90 (Hsp90) expressions in sporadic ccRCC are unknown. Therefore, we analyze the impact of VHL alterations and HIF-α production on the expression of TSC proteins and Hsp90 in these tumors. Alterations in VHL gene region exhibited 37/47 (78.7%) tumors. Monoallelic inactivation (intragenic mutation or LOH) was found in 10 (21...
December 2016: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/27826093/cytokine-and-estrogen-stimulation-of-endothelial-cells-augments-activation-of-the-prekallikrein-high-molecular-weight-kininogen-complex-implications-for-hereditary-angioedema
#11
Kusumam Joseph, Baby G Tholanikunnel, Allen P Kaplan
BACKGROUND: When the prekallikrein-high molecular weight kininogen complex is bound to endothelial cells, prekallikrein is stoichiometrically converted to kallikrein because of release of heat shock protein-90 (Hsp90). Although bradykinin formation is typically initiated by factor XII autoactivation, it is also possible to activate factor XII either by kallikrein, thus formed, or by plasmin. OBJECTIVE: Because attacks of hereditary angioedema can be related to infection and/or exposure to estrogen, we questioned whether estrogen or cytokine stimulation of endothelial cells could augment release of Hsp90 and prekallikrein activation...
November 5, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27825958/simultaneous-blockade-of-interacting-ck2-and-egfr-pathways-by-tumor-targeting-nanobioconjugates-increases-therapeutic-efficacy-against-glioblastoma-multiforme
#12
Szu-Ting Chou, Rameshwar Patil, Anna Galstyan, Pallavi R Gangalum, Webster K Cavenee, Frank B Furnari, Vladimir A Ljubimov, Alexandra Chesnokova, Andrei A Kramerov, Hui Ding, Vida Falahatian, Leila Mashouf, Irving Fox, Keith L Black, Eggehard Holler, Alexander V Ljubimov, Julia Y Ljubimova
Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. GBM tumors are also notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database...
December 28, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/27816945/hsp90-stabilizes-auxin-responsive-phenotypes-by-masking-a-mutation-in-the-auxin-receptor-tir1
#13
Etsuko Watanabe, Shoji Mano, Mika Nomoto, Yasuomi Tada, Ikuko Hara-Nishimura, Mikio Nishimura, Kenji Yamada
Heat shock protein 90 (HSP90) is a molecular chaperone that is required for the function of various substrate proteins, also known as client proteins. It is proposed that HSP90 buffers or hides phenotypic variations in animals and plants by masking mutations in some of its client proteins. However, none of the client proteins with cryptic mutations has been identified to date. Here, we identify the first client protein example by which HSP90 buffers a mutation: the auxin receptor transport inhibitor response 1 (TIR1)...
November 2016: Plant & Cell Physiology
https://www.readbyqxmd.com/read/27807633/-pancreatic-acinar-neoplasms-comparative-molecular-characterization
#14
F Bergmann
Pancreatic acinar cell carcinomas are biologically aggressive neoplasms for which treatment options are very limited. The molecular mechanisms of tumor initiation and progression are largely not understood and precursor lesions have not yet been identified. In this study, pancreatic acinar cell carcinomas were cytogenetically characterized as well as by molecular and immunohistochemical analyses. Corresponding investigations were carried out on pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms augmented by functional analyses...
November 2016: Der Pathologe
https://www.readbyqxmd.com/read/27803431/m3-muscarinic-receptor-signaling-stabilizes-a-novel-mutant-human-ether-a-go-go-related-gene-channel-protein-via-phosphorylation-of-heat-shock-factor-1-in-transfected-cells
#15
Endang Mahati, Peili Li, Yasutaka Kurata, Nani Maharani, Nobuhito Ikeda, Shinji Sakata, Kazuyoshi Ogura, Junichiro Miake, Takeshi Aiba, Wataru Shimizu, Naoe Nakasone, Haruaki Ninomiya, Katsumi Higaki, Kazuhiro Yamamoto, Akira Nakai, Yasuaki Shirayoshi, Ichiro Hisatome
BACKGROUND: Long QT syndrome 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG). Most of its mutations give rise to unstable hERG proteins degraded by the proteasome. Recently, carbachol was reported to stabilize the wild-type hERG-FLAG via activation of the muscarinic type 3 receptor (M3-mAChR). Its action on mutant hERG-FLAG, however, remains uninvestigated.Methods and Results:A novel mutant hERG-FLAG carried 2 mutations: an amino acid substitution G572S and an in-frame insertion D1037_V1038insGD...
November 1, 2016: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/27799162/protein-stabilization-improves-stat3-function-in-autosomal-dominant-hyper-ige-syndrome
#16
Claire E Bocchini, Karen Nahmod, Panagiotis Katsonis, Sang Kim, Moses M Kasembeli, Alexandra Freeman, Olivier Lichtarge, George Makedonas, David J Tweardy
Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by dominant-negative mutations in STAT3; however, the molecular basis for mutant STAT3 allele dysfunction is unclear and treatment remains supportive. We hypothesized that AD-HIES mutations decrease STAT3 protein stability and that mutant STAT3 activity can be improved by agents that increase chaperone protein activity. We used computer modeling to characterize the effect of STAT3 mutations on protein stability. We measured STAT3 protein half-life (t1/2) and determined levels of STAT3 phosphorylated on tyrosine (Y) 705 (pY-STAT3) and mRNA levels of STAT3 gene targets in Epstein-Barr virus-transformed B (EBV) cells, human peripheral blood mononuclear cells (PBMCs), and mouse splenocytes incubated without or with chaperone protein modulators-HSF1A, a small-molecule TRiC modulator, or geranylgeranylacetone (GGA), a drug that upregulates heat shock protein (HSP) 70 and HSP90...
December 29, 2016: Blood
https://www.readbyqxmd.com/read/27791982/erbb2-inhibition-by-lapatinib-promotes-degradation-of-mutant-p53-protein-in-cancer-cells
#17
Dun Li, Natalia D Marchenko
Mutations in the p53 tumor suppressor gene are the most prevalent genetic events in human Her2-positive breast cancer and are associated with poor prognosis and survival. Human clinical data and our in vitro and in vivo studies strongly suggest potent oncogenic cooperation between mutant p53 and Her2 (ErbB2). Yet, the translational significance of mutant p53 in Her2 positive breast cancer, especially with respect to Her2-targeted therapies, has not been evaluated. Our previous work identified novel oncogenic activity of mutant p53 whereby mutp53 amplifies ErbB2 signaling via the mutp53-HSF1-ErbB2 feed-forward loop...
October 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27783598/alternative-modes-of-client-binding-enable-functional-plasticity-of-hsp70
#18
Alireza Mashaghi, Sergey Bezrukavnikov, David P Minde, Anne S Wentink, Roman Kityk, Beate Zachmann-Brand, Matthias P Mayer, Günter Kramer, Bernd Bukau, Sander J Tans
The Hsp70 system is a central hub of chaperone activity in all domains of life. Hsp70 performs a plethora of tasks, including folding assistance, protection against aggregation, protein trafficking, and enzyme activity regulation, and interacts with non-folded chains, as well as near-native, misfolded, and aggregated proteins. Hsp70 is thought to achieve its many physiological roles by binding peptide segments that extend from these different protein conformers within a groove that can be covered by an ATP-driven helical lid...
November 17, 2016: Nature
https://www.readbyqxmd.com/read/27768682/selection-transforms-the-landscape-of-genetic-variation-interacting-with-hsp90
#19
Kerry A Geiler-Samerotte, Yuan O Zhu, Benjamin E Goulet, David W Hall, Mark L Siegal
The protein-folding chaperone Hsp90 has been proposed to buffer the phenotypic effects of mutations. The potential for Hsp90 and other putative buffers to increase robustness to mutation has had major impact on disease models, quantitative genetics, and evolutionary theory. But Hsp90 sometimes contradicts expectations for a buffer by potentiating rapid phenotypic changes that would otherwise not occur. Here, we quantify Hsp90's ability to buffer or potentiate (i.e., diminish or enhance) the effects of genetic variation on single-cell morphological features in budding yeast...
October 2016: PLoS Biology
https://www.readbyqxmd.com/read/27744339/chaperone-families-and-interactions-in-metazoa
#20
Yael Bar-Lavan, Netta Shemesh, Anat Ben-Zvi
Quality control is an essential aspect of cellular function, with protein folding quality control being carried out by molecular chaperones, a diverse group of highly conserved proteins that specifically identify misfolded conformations. Molecular chaperones are thus required to support proteins affected by expressed polymorphisms, mutations, intrinsic errors in gene expression, chronic insult or the acute effects of the environment, all of which contribute to a flux of metastable proteins. In this article, we review the four main chaperone families in metazoans, namely Hsp60 (where Hsp is heat-shock protein), Hsp70, Hsp90 and sHsps (small heat-shock proteins), as well as their co-chaperones...
October 15, 2016: Essays in Biochemistry
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