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Hsp90 mutation

Susana Cedrés, Enriqueta Felip, Cristina Cruz, Ana Martinez de Castro, Nuria Pardo, Alejandro Navarro, Alex Martinez-Marti, Jordin Remon, Jorge Zeron-Medina, Judith Balmaña, Alba Llop-Guevara, Josep M Miquel, Irene Sansano, Paolo Nuciforo, Francesco Mancuso, Violeta Serra, Ana Vivancos
Heat shock proteins (HSPs) are molecular chaperones that maintain proteins in their correct conformation to ensure stability and protect carcinoma cells from apoptosis. HSP90 inhibitors (HSP90i) block multiple targets simultaneously, and despite responses in a selected population, no HSP90i have yet been approved. We present a patient with a lung tumor with an exceptional response to cisplatin/gemcitabine in combination with HSP90i, which nowadays continues with HSP90i maintenance after three years. Whole-exome sequencing of the lung tumor unveiled a BRCA1/2 deficiency mutational signature, and mutation analysis confirmed a germline BRCA1 mutation...
February 26, 2018: Journal of the National Cancer Institute
Yui Konno, Kuta Suzuki, Mizuki Tanaka, Takahiro Shintani, Katsuya Gomi
The Zn2 Cys6 -type transcription factor MalR controls the expression of maltose-utilizing (MAL) cluster genes and the production of amylolytic enzymes in Aspergillus oryzae. In the present study, we demonstrated that MalR formed a complex with Hsp70 and Hsp90 chaperones under non-inducing conditions similar to the yeast counterpart Mal63 and that the complex was released from the chaperone complex after the addition of the inducer maltose. The MalR protein was constitutively localized in the nucleus and mutation in both the putative nuclear localization signals (NLSs) located in the zinc finger motif and the C-terminal region resulted in the loss of nuclear localization...
March 8, 2018: Bioscience, Biotechnology, and Biochemistry
James L Lissemore, Elyse Connors, Ying Liu, Li Qiao, Bing Yang, Mark L Edgley, Stephane Flibotte, Jon Taylor, Vinci Au, Donald G Moerman, Eleanor M Maine
In a genetic screen to identify genes that promote GLP-1/Notch signaling in Caenorhabditis elegans germline stem cells, we found a single mutation, om40 , defining a gene called ego-3. ego-3(om40) causes several defects in the soma and the germline, including paralysis during larval development, sterility, delayed proliferation of germline stem cells, and ectopic germline stem cell proliferation. Whole genome sequencing identified om40 as an allele of hsp-90 , previously known as daf-21 , which encodes the C...
March 5, 2018: G3: Genes—Genomes—Genetics
Sandeep S Joshi, Shunlin Jiang, Emmanual Unni, Stephen R Goding, Tao Fan, Paul A Antony, Thomas J Hornyak
Heat shock protein 90 (HSP90) is a molecular chaperone which stabilizes client proteins with important roles in tumor growth. 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90 ATPase activity, occupies the ATP binding site of HSP90 causing a conformational change which destabilizes client proteins and directs them towards proteosomal degradation. Malignant melanomas have active RAF-MEK-ERK signaling which can occur either through an activating mutation in BRAF (BRAFV600E) or through activation of signal transduction upstream of BRAF...
2018: PloS One
Tom D Bunney, Alison J Inglis, Domenico Sanfelice, Brendan Farrell, Christopher J Kerr, Gary S Thompson, Glenn R Masson, Nethaji Thiyagarajan, Dmitri I Svergun, Roger L Williams, Alexander L Breeze, Matilda Katan
Receptor tyrosine kinase FGFR3 is involved in many signaling networks and is frequently mutated in developmental disorders and cancer. The Hsp90/Cdc37 chaperone system is essential for function of normal and neoplastic cells. Here we uncover the mechanistic inter-relationships between these proteins by combining approaches including NMR, HDX-MS, and SAXS. We show that several disease-linked mutations convert FGFR3 to a stronger client, where the determinant underpinning client strength involves an allosteric network through the N-lobe and at the lobe interface...
February 16, 2018: Structure
Bui Thi Kim Ly, Hoang Thanh Chi
FMS-like tyrosine kinase-3 fragments from exon 14 to the end without any mutations or deletions has been reported to fuse to ETV6 (TEL) in a few cases of myeloid/lymphoid neoplasms with eosinophilia carrying a translocation t(12;13)(p13;q12). This fusion protein confers constitutive activation on FLT3 fragment and induces factor-independent growth in transfected Ba/F3 cells indicating that it is an oncoprotein. However, the mechanism controlling the stability of this oncoprotein is unknown. In this study, we focus on finding factors controlling the stability of ETV6/FLT3...
February 22, 2018: Oncology Research
Dustin Je Huard, Vincent M Crowley, Yuhong Du, Ricardo A Cordova, Zheying Sun, Moya O Tomlin, Chad A Dickey, John Koren, Laura Blair, Haian Fu, Brian S J Blagg, Raquel L Lieberman
Gain-of-function mutations within the olfactomedin (OLF) domain of myocilin result in its toxic intracellular accumulation and hastens the onset of open-angle glaucoma. The absence of myocilin does not cause disease; therefore, strategies aimed at eliminating myocilin could lead to a successful glaucoma treatment. The endoplasmic reticulum Hsp90 paralog Grp94 accelerates OLF aggregation. Knockdown or pharmacological inhibition of Grp94 in cells facilitates clearance of mutant myocilin via a non-proteasomal pathway...
February 5, 2018: ACS Chemical Biology
Anna S Nikonova, Alexander Y Deneka, Anna A Kiseleva, Vladislav Korobeynikov, Anna Gaponova, Ilya G Serebriiskii, Meghan C Kopp, Harvey H Hensley, Tamina N Seeger-Nukpezah, Stefan Somlo, David A Proia, Erica A Golemis
Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance...
January 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Tsu-Yao Cheng, Yi-Chieh Yang, Hsiu-Po Wang, Yu-Wen Tien, Chia-Tung Shun, Hsin-Yi Huang, Michael Hsiao, Kuo-Tai Hua
Pyruvate kinase muscle isozymes (PKMs) have crucial roles in regulating metabolic changes during carcinogenesis. A switch from PKM1 to PKM2 isoform was thought to lead to aerobic glycolysis promoting carcinogenesis, and was considered as one of the cancer signatures. However, recent evidence has argued against the existence of PKM isoform switch and related metabolic effects during cancer progression. We compared the effects of PKM1 and PKM2 in cell invasiveness and metastasis of pancreatic ductal adenocarcinoma (PDAC)...
January 16, 2018: Oncogene
Fabienne C Fiesel, Elle D James, Roman Hudec, Wolfdieter Springer
Loss-of-function mutations in PINK1 or PARKIN are associated with early-onset Parkinson's disease. Upon mitochondrial stress, PINK1 and Parkin together mediate a response that protects cells from the accumulation of harmful, damaged mitochondria. PINK1, the upstream kinase accumulates on the mitochondrial surface and recruits the E3 ubiquitin ligase Parkin on site to ubiquitylate substrate proteins. The joint activity of both to generate phosphorylated poly-ubiquitin chains on the mitochondrial surface induces the recruitment of autophagy receptors and eventually whole organelles are cleared by autophagy...
December 5, 2017: Oncotarget
Heikki Kuusanmäki, Olli Dufva, Elina Parri, Arjan J van Adrichem, Hanna Rajala, Muntasir M Majumder, Bhagwan Yadav, Alun Parsons, Wing C Chan, Krister Wennerberg, Satu Mustjoki, Caroline A Heckman
Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability...
November 14, 2017: Oncotarget
Stuart K Calderwood
Heat shock proteins (HSPs) are found at elevated concentrations in tumour cells, and this increase reflects the proteotoxic stress experienced by the cells due to expanding levels of the mutated oncoproteins that drive tumorigenesis. The protection of oncogenic proteins by HSPs offers a window of vulnerability in tumour metabolism that has been exploited using Hsp90-targeting drugs. Such compounds have been shown to cause inhibition and degradation of a wide range of proteins essential for oncogenesis. Recently, Hsp90 has also been shown to be secreted by tumour cells and to interact in autocrine or paracrine manners with the surfaces of adjacent cells, leading to increased growth and metastasis...
January 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Yoshihiro Ishida, Atsushi Otsuka, Kenji Kabashima
PURPOSE OF REVIEW: The present review aims to provide readers with the latest updates on the biology and clinical management of cutaneous angiosarcoma (cAS). RECENT FINDINGS: The genomic alteration of cAS is heterogeneous. Mutations are enriched in the mitosis-activated kinase (MAPK) pathway. Functional analysis has identified molecules that may serve as potential markers and therapeutic targets of angiosarcoma. These molecules include survivin, HSP90, FOXM1, miR-497-5p, KCa3...
March 2018: Current Opinion in Oncology
Ödül Karayazi Atici, Anna Urbanska, Sesha Gopal Gopinathan, Florence Boutillon, Vincent Goffin, Carrie S Shemanko
Prolactin (PRL) acts as a survival factor for breast cancer cells, but the PRL signaling pathway and the mechanism are unknown. Previously, we identified the master chaperone, heat shock protein 90 (HSP90) α, as a prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) target gene involved in survival, and here we investigated the role of HSP90 in the mechanism of PRL-induced viability in response to DNA damage. The ataxia-telangiectasia mutated kinase (ATM) protein plays a critical role in the cellular response to double-strand DNA damage...
February 1, 2018: Endocrinology
Benjamin K Gibbs, Carole Sourbier
Heat shock protein 90 (HSP90) is a molecular chaperone necessary for the folding and proper function of multiple "client" proteins. HSP90 is involved in numerous biological processes and is critical to maintain proteostasis and to protect the cells from potentially harmful environmental stresses such as heat. However, in cancer, the role of HSP90, and other molecular chaperones, is corrupted as many of HSP90 clients are kinases and transcription factors whose aberrant activation or mutation drives tumor growth...
2018: Methods in Molecular Biology
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
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
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
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
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
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