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Hsp90 mutation

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https://www.readbyqxmd.com/read/28532230/hsp90-stabilizes-auxin-receptor-tir1-and-ensures-plasticity-of-auxin-responses
#1
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 22, 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
#2
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
#3
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
https://www.readbyqxmd.com/read/28438176/the-pink1-p-i368n-mutation-affects-protein-stability-and-ubiquitin-kinase-activity
#4
Maya Ando, Fabienne C Fiesel, Roman Hudec, Thomas R Caulfield, Kotaro Ogaki, Paulina Górka-Skoczylas, Dariusz Koziorowski, Andrzej Friedman, Li Chen, Valina L Dawson, Ted M Dawson, Guojun Bu, Owen A Ross, Zbigniew K Wszolek, Wolfdieter Springer
BACKGROUND: Mutations in PINK1 and PARKIN are the most common causes of recessive early-onset Parkinson's disease (EOPD). Together, the mitochondrial ubiquitin (Ub) kinase PINK1 and the cytosolic E3 Ub ligase PARKIN direct a complex regulated, sequential mitochondrial quality control. Thereby, damaged mitochondria are identified and targeted to degradation in order to prevent their accumulation and eventually cell death. Homozygous or compound heterozygous loss of either gene function disrupts this protective pathway, though at different steps and by distinct mechanisms...
April 24, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28415650/a-highly-conserved-redox-active-mx-2-cwx-6-r-motif-regulates-zap70-stability-and-activity
#5
Christoph Thurm, Mateusz P Poltorak, Elisa Reimer, Melanie M Brinkmann, Lars Leichert, Burkhart Schraven, Luca Simeoni
ζ-associated protein of 70 kDa (Zap70) is crucial for T-cell receptor (TCR) signaling. Loss of Zap70 in both humans and mice results in severe immunodeficiency. On the other hand, the expression of Zap70 in B-cell malignancies correlates with the severity of the disease. Because of its role in immune-related disorders, Zap70 has become a therapeutic target for the treatment of human diseases. It is well-established that the activity/expression of Zap70 is regulated by post-translational modifications of crucial amino acids including the phosphorylation of tyrosines and the ubiquitination of lysines...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28395559/management-of-myelofibrosis-jak-inhibition-and-beyond
#6
Maximilian Stahl, Amer M Zeidan
Myelofibrosis (MF) is characterized by bone marrow fibrosis with subsequent extramedullary hematopoiesis and abnormal cytokine expression leading to splenomegaly, constitutional symptoms and cytopenias. The discovery of the JAK2 V617F mutation in the majority of MF patients has been followed by significant progress in drug development for MF. Areas covered: In this article, we review advances in the understanding of the underlying disease biology, prognostic assessment and therapeutic modalities for MF. We provide clinical trial evidence behind using the JAK2 inhibitor ruxolitinib, erythropoiesis stimulating agents, androgens, immunomodulatory drugs, interferon, cytoreductive drugs and hypomethylating agents in MF...
April 26, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28320779/the-g2385r-risk-factor-for-parkinson-s-disease-enhances-chip-dependent-intracellular-degradation-of-lrrk2
#7
Iakov N Rudenko, Alice Kaganovich, Rebekah G Langston, Aleksandra Beilina, Kelechi Ndukwe, Ravindran Kumaran, Allissa A Dillman, Ruth Chia, Mark R Cookson
Autosomal dominant mutations in leucine-rich repeat kinase 2 ( LRRK2 ) are associated with Parkinson's disease (PD). Most pathogenic LRRK2 mutations result in amino-acid substitutions in the central ROC-COR-Kinase triple domain and affect enzymatic functions of the protein. However, there are several variants in LRRK2 , including the risk factor G2385R, that impact PD pathogenesis by unknown mechanisms. Previously, we have shown that G2385R LRRK2 has decreased kinase activity in vitro and altered affinity to LRRK2 interactors...
March 20, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28302086/extracellular-hsp90-and-tgf%C3%AE-regulate-adhesion-migration-and-anchorage-independent-growth-in-a-paired-colon-cancer-cell-line-model
#8
Jo-Anne de la Mare, Tamarin Jurgens, Adrienne L Edkins
BACKGROUND: Tumour metastasis remains the major cause of death in cancer patients and, to date, the mechanism and signalling pathways governing this process are not completely understood. The TGF-β pathway is the most commonly mutated pathway in cancer, however its role in cancer progression is controversial as it can function as both a promoter and a suppressor of metastasis. Although previous studies have suggested a role for the molecular chaperone Hsp90 in regulating the TGF-β pathway, the level at which this occurs as well as the consequences in terms of colon cancer metastasis are unknown...
March 16, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28290541/hsp90-dependence-of-a-kinase-is-determined-by-its-conformational-landscape
#9
Qi Luo, Edgar E Boczek, Qi Wang, Johannes Buchner, Ville R I Kaila
Heat shock protein 90 (Hsp90) is an abundant molecular chaperone, involved in the folding and activation of 60% of the human kinome. The oncogenic tyrosine kinase v-Src is one of the most stringent client proteins of Hsp90, whereas its almost identical homolog c-Src is only weakly affected by the chaperone. Here, we perform atomistic molecular simulations and in vitro kinase assays to explore the mechanistic differences in the activation of v-Src and c-Src. While activation in c-Src is strictly controlled by ATP-binding and phosphorylation, we find that activating conformational transitions are spontaneously sampled in Hsp90-dependent Src mutants...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28278223/the-structure-of-fkbp38-in-complex-with-the-meevd-tetratricopeptide-binding-motif-of-hsp90
#10
Katie L I M Blundell, Mohinder Pal, S Mark Roe, Laurence H Pearl, Chrisostomos Prodromou
Tetratricopeptide (TPR) domains are known protein interaction domains. We show that the TPR domain of FKBP8 selectively binds Hsp90, and interactions upstream of the conserved MEEVD motif are critical for tight binding. In contrast FKBP8 failed to bind intact Hsp70. The PPIase domain was not essential for the interaction with Hsp90 and binding was completely encompassed by the TPR domain alone. The conformation adopted by Hsp90 peptides, containing the conserved MEEVD motif, in the crystal structure were similar to that seen for the TPR domains of CHIP, AIP and Tah1...
2017: PloS One
https://www.readbyqxmd.com/read/28275054/drosophila-canopy-b-is-a-cochaperone-of-glycoprotein-93
#11
Crystal Morales, Zihai Li
Drosophila gp93 was identified as the ortholog of the mammalian endoplasmic reticulum-resident chaperone gp96. gp93 was found capable of rescuing gp96 client proteins, such as Toll-like receptors (TLRs) and integrins, in a gp96-deficient murine cell line. Mammalian gp96 was further found to require the cochaperone canopy 3 (CNPY3) for proper folding and expression of TLRs, but not integrins. In Drosophila, two possible CNPY family members have been identified but have not yet been characterized. Therefore, we sought to determine the role of Drosophila CNPYa and CNPYb in gp93 biology...
April 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28265807/association-of-heat-stress-protein-90-and-70-gene-polymorphism-with-adaptability-traits-in-indian-sheep-ovis-aries
#12
K M Singh, S Singh, I Ganguly, Raja K Nachiappan, A Ganguly, R Venkataramanan, A Chopra, H K Narula
Heat stress proteins assist cellular proteins in the acquisition of native structure. The present research was conducted to study how thermo-tolerance is modulated by HSP90 and HSP70 gene polymorphism and its association with hemato-physio-biochemical parameters, supported by their expression profiles in Chokla, Magra, Marwari, and Madras Red sheep breeds. Least square analysis revealed significant effect (P < 0.05) of season and breed on all the physiological parameters, i.e., temperature, respiratory rate, and pulse rate (a...
March 6, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28255869/aryl-hydrocarbon-receptor-interacting-protein-aip-n-terminus-gene-mutations-identified-in-pituitary-adenoma-patients-alter-protein-stability-and-function
#13
Robert Formosa, Josanne Vassallo
Mutations spanning the entire aryl hydrocarbon receptor-interacting protein (AIP) gene have been found in isolated familial cases of pituitary adenomas (PA). Missense mutations located in the N-terminus of the gene have been identified in several patients. However, the functional significance of these mutations remains a matter of controversy. In most studies, the N-terminus of AIP has been shown to regulate protein stability and subcellular localization of the AIP-AHR-HSP90 complex but not to be involved in protein-protein interactions...
March 2, 2017: Hormones & Cancer
https://www.readbyqxmd.com/read/28248920/genome-wide-barcoded-transposon-screen-for-cancer-drug-sensitivity-in-haploid-mouse-embryonic-stem-cells
#14
Stephen J Pettitt, Dragomir B Krastev, Helen N Pemberton, Yari Fontebasso, Jessica Frankum, Farah L Rehman, Rachel Brough, Feifei Song, Ilirjana Bajrami, Rumana Rafiq, Fredrik Wallberg, Iwanka Kozarewa, Kerry Fenwick, Javier Armisen-Garrido, Amanda Swain, Aditi Gulati, James Campbell, Alan Ashworth, Christopher J Lord
We describe a screen for cellular response to drugs that makes use of haploid embryonic stem cells. We generated ten libraries of mutants with piggyBac gene trap transposon integrations, totalling approximately 100,000 mutant clones. Random barcode sequences were inserted into the transposon vector to allow the number of cells bearing each insertion to be measured by amplifying and sequencing the barcodes. These barcodes were associated with their integration sites by inverse PCR. We exposed these libraries to commonly used cancer drugs and profiled changes in barcode abundance by Ion Torrent sequencing in order to identify mutations that conferred sensitivity...
March 1, 2017: Scientific Data
https://www.readbyqxmd.com/read/28215707/hsp90-shapes-the-consequences-of-human-genetic-variation
#15
Georgios I Karras, Song Yi, Nidhi Sahni, Máté Fischer, Jenny Xie, Marc Vidal, Alan D D'Andrea, Luke Whitesell, Susan Lindquist
HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90 ≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function...
February 23, 2017: Cell
https://www.readbyqxmd.com/read/28176794/x-linked-primary-ciliary-dyskinesia-due-to-mutations-in-the-cytoplasmic-axonemal-dynein-assembly-factor-pih1d3
#16
Chiara Olcese, Mitali P Patel, Amelia Shoemark, Santeri Kiviluoto, Marie Legendre, Hywel J Williams, Cara K Vaughan, Jane Hayward, Alice Goldenberg, Richard D Emes, Mustafa M Munye, Laura Dyer, Thomas Cahill, Jeremy Bevillard, Corinne Gehrig, Michel Guipponi, Sandra Chantot, Philippe Duquesnoy, Lucie Thomas, Ludovic Jeanson, Bruno Copin, Aline Tamalet, Christel Thauvin-Robinet, Jean-François Papon, Antoine Garin, Isabelle Pin, Gabriella Vera, Paul Aurora, Mahmoud R Fassad, Lucy Jenkins, Christopher Boustred, Thomas Cullup, Mellisa Dixon, Alexandros Onoufriadis, Andrew Bush, Eddie M K Chung, Stylianos E Antonarakis, Michael R Loebinger, Robert Wilson, Miguel Armengot, Estelle Escudier, Claire Hogg, Serge Amselem, Zhaoxia Sun, Lucia Bartoloni, Jean-Louis Blouin, Hannah M Mitchison
By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2-DNAAF4-HSP90 complex akin to the HSP90 co-chaperone R2TP complex...
February 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28167505/acquired-resistance-to-the-hsp90-inhibitor-ganetespib-in-kras-mutant-nsclc-is-mediated-via-reactivation-of-the-erk-p90rsk-mtor-signaling-network
#17
Suman Chatterjee, Eric H-B Huang, Ian Christie, Brenda F Kurland, Timothy F Burns
Approximately 25% of non-small cell lung cancer (NSCLC) patients have KRAS mutations, and no effective therapeutic strategy exists for these patients. The use of Hsp90 inhibitors in KRAS-mutant NSCLC appeared to be a promising approach, as these inhibitors target many KRAS downstream effectors; however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations, which may prevent and overcome resistance to Hsp90 inhibitors...
May 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28153791/hdac6-deacetylates-p53-at-lysines-381-382-and-differentially-coordinates-p53-induced-apoptosis
#18
Hyun-Wook Ryu, Dong-Hee Shin, Dong Hoon Lee, Junjeong Choi, Gyoonhee Han, Kang Young Lee, So Hee Kwon
HDAC6-selective inhibitors represent promising new cancer therapeutic agents, but their precise mechanisms of action are not well understood. In particular, p53's role in HDAC6 inhibitor-induced effects has not been fully elucidated. In this study, we show that an HDAC6-selective inhibitor, A452, increased wild-type p53 levels by destabilizing MDM2, but decreased mutant p53 by inducing MDM2 and inhibiting Hsp90-mutant p53 complex formation. Interestingly, HDAC6 levels inversely correlated with p53 acetylation at lysines 381/382 associated with p53 functional activation...
April 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28139700/the-crystal-structure-of-the-sgt1-skp1-complex-the-link-between-hsp90-and-both-scf-e3-ubiquitin-ligases-and-kinetochores
#19
Oliver Willhoft, Richard Kerr, Dipali Patel, Wenjuan Zhang, Caezar Al-Jassar, Tina Daviter, Stefan H Millson, Konstantinos Thalassinos, Cara K Vaughan
The essential cochaperone Sgt1 recruits Hsp90 chaperone activity to a range of cellular factors including SCF E3 ubiquitin ligases and the kinetochore in eukaryotes. In these pathways Sgt1 interacts with Skp1, a small protein that heterodimerizes with proteins containing the F-box motif. We have determined the crystal structure of the interacting domains of Saccharomyces cerevisiae Sgt1 and Skp1 at 2.8 Å resolution and validated the interface in the context of the full-length proteins in solution. The BTB/POZ domain of Skp1 associates with Sgt1 via the concave surface of its TPR domain using residues that are conserved in humans...
January 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28138075/transposable-element-mediated-balancing-selection-at-hsp90-underlies-embryo-developmental-variation
#20
Bing Chen, Bo Zhang, Lingling Xu, Qing Li, Feng Jiang, Pengcheng Yang, Yanan Xu, Le Kang
Understanding the roles of transposable elements (TEs) in the evolution of genome and adaptation is a long-sought goal. Here, we present a new model of TE co-option, in which a TE is harnessed by an essential gene and confers local adaptation through heterozygote advantage. We characterized a human Alu-like TE family, the Lm1 elements, in the genome of the migratory locust Locusta migratoria that harbors 0.7 million copies of the elements. Scanning Lm1 insertions in the natural locust populations revealed the widespread high polymorphism of Lm1...
May 1, 2017: Molecular Biology and Evolution
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