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https://www.readbyqxmd.com/read/29113809/mir21-drives-resistance-to-heat-shock-protein-90-inhibition-in-cholangiocarcinoma
#1
Andrea Lampis, Pietro Carotenuto, Georgios Vlachogiannis, Luciano Cascione, Somaieh Hedayat, Rosemary Burke, Paul Clarke, Else Bosma, Michele Simbolo, Aldo Scarpa, Sijia Yu, Rebecca Cole, Elizabeth Smyth, Javier Fernández Mateos, Ruwaida Begum, Blanka Hezelova, Zakaria Eltahir, Andrew Wotherspoon, Nicos Fotiadis, Maria Antonietta Bali, Chirag Nepal, Khurum Khan, Mark Stubbs, Jens C Hahne, Pierluigi Gasparini, Vincenza Guzzardo, Carlo M Croce, Suzanne Eccles, Matteo Fassan, David Cunningham, Jesper B Andersen, Paul Workman, Nicola Valeri, Chiara Braconi
BACKGROUND & AIMS: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. METHODS: We performed a high-throughput screen of 484 small molecule compounds to identify those that reduced viability of 6 human CCA cell lines...
November 4, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29110400/spaghetti-a-homolog-of-human-rpap3-rna-polymerase-ii-associated-protein-3-determines-the-fate-of-germline-stem-cells-in-drosophila-ovary
#2
Dongsheng Chen, Xiaoqian Tao, Lijuan Zhou, Fuling Sun, Mingzhong Sun, Xin Fang
The Drosophila ovary provides an attractive model for studying the extrinsic or intrinsic factors that regulate the fate of germline stem cells (GSCs). Using this model, we identified a new role for Drosophila spaghetti (spag), encoding a homolog of human RNA polymerase II-associated protein 3 (RPAP3), in regulating the fate of ovarian GSCs. Results from spag knockdown and genetic mosaic studies suggest that spag functions as an intrinsic factor for GSCs maintenance. Loss of Spag by, either spag RNAi or null mutation failed to trigger apoptosis in ovarian GSCs...
November 7, 2017: Cell Biology International
https://www.readbyqxmd.com/read/29095844/ensemble-based-modeling-and-rigidity-decomposition-of-allosteric-interaction-networks-and-communication-pathways-in-cyclin-dependent-kinases-differentiating-kinase-clients-of-the-hsp90-cdc37-chaperone
#3
Gabrielle Stetz, Amanda Tse, Gennady M Verkhivker
The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences...
2017: PloS One
https://www.readbyqxmd.com/read/28973376/the-integrity-and-organization-of-the-human-aipl1-functional-domains-is-critical-for-its-role-as-a-hsp90-dependent-co-chaperone-for-rod-pde6
#4
Almudena Sacristan-Reviriego, James Bellingham, Chrisostomos Prodromou, Neruban Kumaran, James Bainbridge, Michel Michaelides, Jacqueline van der Spuy
Biallelic mutations in the photoreceptor-expressed aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) are associated with autosomal recessive Leber congenital amaurosis (LCA), the most severe form of inherited retinopathy in early childhood. AIPL1 functions as a photoreceptor-specific co-chaperone that interacts with the molecular chaperone HSP90 to facilitate the stable assembly of the retinal cyclic GMP (cGMP) phosphodiesterase (PDE6) holoenzyme. In this study, we characterized the functional deficits of AIPL1 variations, some of which induce aberrant pre-mRNA AIPL1 splicing leading to the production of alternative AIPL1 isoforms...
November 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28970102/the-proteome-speciation-of-an-immortalized-cystic-fibrosis-cell-line-new-perspectives-on-the-pathophysiology-of-the-disease
#5
Michele Puglia, Claudia Landi, Assunta Gagliardi, Loretta Breslin, Alessandro Armini, Jlenia Brunetti, Alessandro Pini, Laura Bianchi, Luca Bini
Cystic Fibrosis (CF) is a recessively inherited disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR has a pivotal role in the onset of CF, and several proteins are involved in its homeostasis. To study CFTR interactors at protein species level, we used a functional proteomics approach combining 2D-DIGE, mass spectrometry and enrichment analysis. A human bronchial epithelial cell line with cystic fibrosis (CFBE41o-) and the control (16HBE14o-) were used for the comparison...
January 6, 2018: Journal of Proteomics
https://www.readbyqxmd.com/read/28915917/translocation-of-molecular-chaperones-to-the-titin-springs-is-common-in-skeletal-myopathy-patients-and-affects-sarcomere-function
#6
Andreas Unger, Lisa Beckendorf, Pierre Böhme, Rudolf Kley, Marion von Frieling-Salewsky, Hanns Lochmüller, Rolf Schröder, Dieter O Fürst, Matthias Vorgerd, Wolfgang A Linke
Myopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g., myofiber metabolism and contractile properties. In this study, we observed increased passive tension (PT) of skinned myofibers from patients with myofibrillar myopathy (MFM) caused by FLNC mutations (MFM-filaminopathy) and limb-girdle muscular dystrophy type-2A due to CAPN3 mutations (LGMD2A), compared to healthy control myofibers. Because the giant protein titin determines myofiber PT, we measured its molecular size and the titin-to-myosin ratio, but found no differences between myopathies and controls...
September 15, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28870917/the-association-between-hsp90-topoisomerase-i-immunophenotype-and-the-clinical-features-of-colorectal-cancers-in-respect-to-kras-gene-status
#7
Julia K Bar, Anna Lis-Nawara, Piotr Grelewski, Leszek Noga, Zygmunt Grzebieniak, Michał Jeleń
AIM: The aim of this study was to investigate heat shock protein 90 (HSP90) and topoisomerase I (Topo I) expression and the association between both proteins and clinicopathological parameters of colorectal cancer (CRC), in order to describe their role in tumor biology regarding to Kirsten Ras (KRAS) - positive/negative cases. MATERIALS AND METHODS: Expression of HSP90 and Topo I, and KRAS gene mutations were estimated in primary CRCs. RESULTS: HSP90/Topo I immunophenotype correlated with gender, Duke staging, tumor grade and lymph node metastasis (p<0...
September 2017: Anticancer Research
https://www.readbyqxmd.com/read/28855508/chaperones-rescue-the-energetic-landscape-of-mutant-cftr-at-single-molecule-and-in-cell
#8
Miklos Bagdany, Guido Veit, Ryosuke Fukuda, Radu G Avramescu, Tsukasa Okiyoneda, Imad Baaklini, Jay Singh, Guy Sovak, Haijin Xu, Pirjo M Apaja, Sara Sattin, Lenore K Beitel, Ariel Roldan, Giorgio Colombo, William Balch, Jason C Young, Gergely L Lukacs
Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperature-sensitive mutant cystic fibrosis channel (∆F508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 °C and concomitant functional inactivation of ∆F508-CFTR are partially suppressed by constitutive activity of Hsc70 and Hsp90 chaperone/co-chaperone at the plasma membrane and post-endoplasmic reticulum compartments in vivo, and at single-molecule level in vitro, indicated by kinetic and thermodynamic remodeling of the mutant gating energetics toward its wild-type counterpart...
August 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28822683/hsp90-sensitivity-to-adp-reveals-hidden-regulation-mechanisms
#9
Jackson C Halpin, Timothy O Street
The ATPase cycle of the Hsp90 molecular chaperone is essential for maintaining the stability of numerous client proteins. Extensive analysis has focused on ATP-driven conformational changes of Hsp90; however, little is known about how Hsp90 operates under physiological nucleotide conditions in which both ATP and ADP are present. By quantifying Hsp90 activity under mixed nucleotide conditions, we find dramatic differences in ADP sensitivity among Hsp90 homologs. ADP acts as a strong ATPase inhibitor of cytosol-specific Hsp90 homologs, whereas organellular Hsp90 homologs (Grp94 and TRAP1) are relatively insensitive to the presence of ADP...
September 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28804127/discovery-of-novel-drug-sensitivities-in-t-pll-by-high-throughput-ex-vivo-drug-testing-and-mutation-profiling
#10
E I Andersson, S Pützer, B Yadav, O Dufva, S Khan, L He, L Sellner, A Schrader, G Crispatzu, M Oleś, H Zhang, S Adnan-Awad, S Lagström, D Bellanger, J P Mpindi, S Eldfors, T Pemovska, P Pietarinen, A Lauhio, K Tomska, C Cuesta-Mateos, E Faber, S Koschmieder, T H Brümmendorf, S Kytölä, E-R Savolainen, T Siitonen, P Ellonen, O Kallioniemi, K Wennerberg, W Ding, M-H Stern, W Huber, S Anders, J Tang, T Aittokallio, T Zenz, M Herling, S Mustjoki
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles...
August 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28797845/the-hsp90-inhibitor-nvp-auy922-attenuates-intrinsic-pi3k-inhibitor-resistance-in-kras-mutant-non-small-cell-lung-cancer
#11
Kang-Seo Park, Hannah Yang, Junyoung Choi, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Hanwool Jeon, Sang-We Kim, Dae Ho Lee
More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway...
October 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28782530/chemotherapeutics-resistance-arms-race-an-update-on-mechanisms-involved-in-resistance-limiting-egfr-inhibitors-in-lung-cancer
#12
REVIEW
Pankaj Kumar Singh, Om Silakari
Clinical reports suggest that EGFR-mutated lung cancer usually respond significantly towards small molecule tyrosine kinase inhibitors. Same studies also report the eventual development of acquired resistance within a median time interval of 9 to 14months. One of the major mechanisms involved in this acquired resistance was found to be a secondary point mutation at gate-keeper residue, EGFR T790M. However, there are other recent studies which disclose the role of few other novel key players such as, ZEB1, TOPK etc...
October 1, 2017: Life Sciences
https://www.readbyqxmd.com/read/28765916/low-co-expression-of-epidermal-growth-factor-receptor-and-its-chaperone-heat-shock-protein-90-is-associated-with-worse-prognosis-in-primary-glioblastoma-idh-wild-type
#13
Elsa Sartori, Rupert Langer, Erik Vassella, Ekkehard Hewer, Philippe Schucht, Inti Zlobec, Sabina Berezowska
Epidermal growth factor receptor (EGFR) is a major oncogenic driver in glioblastoma (GBM) without mutations in the isocitrate dehydrogenase gene (IDH-wildtype). Heat shock protein 90 (HSP90) is a regulator of the stability of oncogenic proteins including EGFR, thereby acting as a molecular chaperone. We investigated the expression of EGFR and its chaperone HSP90 in GBM, IDH-wildtype. Tissue availability permitted analysis of 237/449 consecutive GBM cases, among them 214 IDH-wildtype (90.3%). The expression of EGFR and HSP90 was analysed by immunohistochemistry on a tissue microarray containing various tumour regions...
August 1, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28743892/dyrk1b-mutations-associated-with-metabolic-syndrome-impair-the-chaperone-dependent-maturation-of-the-kinase-domain
#14
Samira Abu Jhaisha, Esti W Widowati, Isao Kii, Rie Sonamoto, Stefan Knapp, Chrisovalantis Papadopoulos, Walter Becker
Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28738064/species-a-rotavirus-nsp3-acquires-its-translation-inhibitory-function-prior-to-stable-dimer-formation
#15
Hugo I Contreras-Treviño, Edgar Reyna-Rosas, Renato León-Rodríguez, Blanca H Ruiz-Ordaz, Tzvetanka D Dinkova, Ana M Cevallos, Luis Padilla-Noriega
Species A rotavirus non-structural protein 3 (NSP3) is a translational regulator that inhibits or, under some conditions, enhances host cell translation. NSP3 binds to the translation initiation factor eIF4G1 and evicts poly-(A) binding protein (PABP) from eIF4G1, thus inhibiting translation of polyadenylated mRNAs, presumably by disrupting the effect of PABP bound to their 3'-ends. NSP3 has a long coiled-coil region involved in dimerization that includes a chaperone Hsp90-binding domain (HS90BD). We aimed to study the role in NSP3 dimerization of a segment of the coiled-coil region adjoining the HS90BD...
2017: PloS One
https://www.readbyqxmd.com/read/28673392/mechanisms-of-resistance-to-jak2-inhibitors-in-myeloproliferative-neoplasms
#16
REVIEW
Sara C Meyer
Myeloproliferative neoplasms are driven by activated JAK2 signaling due to somatic mutations in JAK2, the thrombopoietin receptor MPL or the chaperone calreticulin in hematopoietic stem/progenitor cells. JAK2 inhibitors have been developed, but despite clinical benefits, they do not signficantly reduce the mutant clone. Loss of response to JAK2 inhibitors occurs and several mechanisms of resistance, genetic and functional, have been identified. Resistance mutations have not been reported in MPN patients suggesting incomplete target inhibition...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28637869/heat-shock-proteins-stimulate-apobec-3-mediated-cytidine-deamination-in-the-hepatitis-b-virus
#17
COMPARATIVE STUDY
Zhigang Chen, Thomas L Eggerman, Alexander V Bocharov, Irina N Baranova, Tatyana G Vishnyakova, Roger Kurlander, Amy P Patterson
Apolipoprotein B mRNA-editing enzyme catalytic subunit 3 (APOBEC-3) enzymes are cytidine deaminases that are broadly and constitutively expressed. They are often up-regulated during carcinogenesis and candidate genes for causing the major single-base substitution in cancer-associated DNA mutations. Moreover, APOBEC-3s are involved in host innate immunity against many viruses. However, how APOBEC-3 mutational activity is regulated in normal and pathological conditions remains largely unknown. Heat shock protein levels are often elevated in both carcinogenesis and viral infection and are associated with DNA mutations...
August 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28636940/hectd3-mediates-an-hsp90-dependent-degradation-pathway-for-protein-kinase-clients
#18
Zhaobo Li, Lihong Zhou, Chrisostomos Prodromou, Velibor Savic, Laurence H Pearl
Inhibition of the ATPase cycle of the HSP90 chaperone promotes ubiquitylation and proteasomal degradation of its client proteins, which include many oncogenic protein kinases. This provides the rationale for HSP90 inhibitors as cancer therapeutics. However, the mechanism by which HSP90 ATPase inhibition triggers ubiquitylation is not understood, and the E3 ubiquitin ligases involved are largely unknown. Using a siRNA screen, we have identified components of two independent degradation pathways for the HSP90 client kinase CRAF...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28634279/in-frame-seven-amino-acid-duplication-in-aip-arose-over-the-last-3000-years-disrupts-protein-interaction-and-stability-and-is-associated-with-gigantism
#19
Roberto Salvatori, Serban Radian, Yoan Diekmann, Donato Iacovazzo, Alessia David, Plamena Gabrovska, Giorgia Grassi, Anna-Marie Bussell, Karen Stals, Astrid Weber, Richard Quinton, Elizabeth C Crowne, Valentina Corazzini, Lou Metherell, Tara Kearney, Daniel Du Plessis, Ajay Kumar Sinha, Atik Baborie, Anne-Lise Lecoq, Philippe Chanson, Olaf Ansorge, Sian Ellard, Peter J Trainer, David Balding, Mark G Thomas, Márta Korbonits
OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. DESIGN AND METHODS: Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments...
September 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/28619760/fbw7-dependent-mcl-1-degradation-mediates-the-anticancer-effect-of-hsp90-inhibitors
#20
Jingshan Tong, Shuai Tan, Zaneta Nikolovska-Coleska, Jian Yu, Fangdong Zou, Lin Zhang
Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well-understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors...
September 2017: Molecular Cancer Therapeutics
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