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https://www.readbyqxmd.com/read/28915917/translocation-of-molecular-chaperones-to-the-titin-springs-is-common-in-skeletal-myopathy-patients-and-affects-sarcomere-function
#1
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
#2
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
#3
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
#4
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...
August 16, 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
#5
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
#6
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...
August 7, 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
#7
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...
August 4, 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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/28566436/reactivation-of-the-p90rsk-cdc25c-pathway-leads-to-bypass-of-the-ganetespib-induced-g2-m-arrest-and-mediates-acquired-resistance-to-ganetespib-in-kras-mutant-nsclc
#16
Suman Chatterjee, Eric H-B Huang, Ian Christie, Timothy F Burns
A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit...
August 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28539411/substrate-binding-by-the-yeast-hsp110-nucleotide-exchange-factor-and-molecular-chaperone-sse1-is-not-obligate-for-its-biological-activities
#17
Veronica M Garcia, Nadinath B Nillegoda, Bernd Bukau, Kevin A Morano
The highly conserved heat shock protein 70 (Hsp70) is a ubiquitous molecular chaperone essential for maintaining cellular protein homeostasis. The related protein Hsp110 (Sse1/Sse2 in Saccharomyces cerevisiae) functions as a nucleotide exchange factor (NEF) to regulate the protein folding activity of Hsp70. Hsp110/Sse1 also can prevent protein aggregation in vitro via its substrate-binding domain (SBD), but the cellular roles of this "holdase" activity are poorly defined. We generated and characterized an Sse1 mutant that separates, for the first time, its nucleotide exchange and substrate-binding functions...
July 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28532230/hsp90-stabilizes-auxin-receptor-tir1-and-ensures-plasticity-of-auxin-responses
#18
Etsuko Watanabe, Shoji Mano, Ikuko Hara-Nishimura, Mikio Nishimura, Kenji Yamada
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of target proteins. Here, we report that the auxin receptor TIR1 is a target of cytosolic HSP90 and that HSP90 and TIR1 form a complex. Inhibition of HSP90 compromised the nuclear localization of TIR1, and abrogated plant responses to the hormone auxin. Our findings suggest that HSP90 positively regulates auxin receptor function. We also propose that HSP90 buffers or hides phenotypic variations in animals and plants by masking mutations in some of its target proteins...
May 4, 2017: Plant Signaling & Behavior
https://www.readbyqxmd.com/read/28453558/tumor-targeted-sn38-inhibits-growth-of-early-stage-non-small-cell-lung-cancer-nsclc-in-a-kras-p53-transgenic-mouse-model
#19
Alexander Y Deneka, Leora Haber, Meghan C Kopp, Anna V Gaponova, Anna S Nikonova, Erica A Golemis
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, with a 5-year survival of only ~16%. Potential strategies to address NSCLC mortality include improvements in early detection and prevention, and development of new therapies suitable for use in patients with early and late stage diagnoses. Controlling the growth of early stage tumors could yield significant clinical benefits for patients with comorbidities that make them poor candidates for surgery: however, many drugs that limit cancer growth are not useful in the setting of long-term use or in comorbid patients, because of associated toxicities...
2017: PloS One
https://www.readbyqxmd.com/read/28450729/collateral-sensitivity-networks-reveal-evolutionary-instability-and-novel-treatment-strategies-in-alk-mutated-non-small-cell-lung-cancer
#20
Andrew Dhawan, Daniel Nichol, Fumi Kinose, Mohamed E Abazeed, Andriy Marusyk, Eric B Haura, Jacob G Scott
Drug resistance remains an elusive problem in cancer therapy, particularly for novel targeted therapies. Much work is focused upon the development of an arsenal of targeted therapies, towards oncogenic driver genes such as ALK-EML4, to overcome the inevitable resistance that develops over time. Currently, after failure of first line ALK TKI therapy, another ALK TKI is administered, though collateral sensitivity is not considered. To address this, we evolved resistance in an ALK rearranged non-small cell lung cancer line (H3122) to a panel of 4 ALK TKIs, and performed a collateral sensitivity analysis...
April 27, 2017: Scientific Reports
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