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Hsp90 mutation

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
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
Torsten Will, Henrike Schmidtberg, Marisa Skaljac, Andreas Vilcinskas
Heat shock protein 83 (HSP83) is homologous to the chaperone HSP90. It has pleiotropic functions in Drosophila melanogaster, including the control of longevity and fecundity, and facilitates morphological evolution by buffering cryptic deleterious mutations in wild populations. In the pea aphid Acyrthosiphon pisum, HSP83 expression is moderately induced by bacterial infection but upregulated more strongly in response to heat stress and fungal infection. Stress-inducible heat shock proteins are of considerable evolutionary and ecological importance because they are known to buffer environmental variation and to influence fitness under non-optimal conditions...
October 14, 2016: Development Genes and Evolution
Caron Jacobson, Nadja Kopp, Jacob V Layer, Robert A Redd, Sebastian Tschuri, Sarah Haebe, Diederik van Bodegom, Liat Bird, Amanda L Christie, Alexandra Christodoulou, Amy Saur, Trevor Tivey, Stefanie Zapf, Deepak Bararia, Ursula Zimber-Strobl, Scott J Rodig, Oliver Weigert, David M Weinstock
The BTK inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma. Intrinsic resistance can occur through activation of the non-classical NFκB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer HSP90 inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IKKα in MCL lines and CD40-dependent B cells, with downstream loss of MAP kinase and non-classical NFκB signaling...
October 14, 2016: Blood
Jürgen Fritsch, Ricarda Fickers, Jan Klawitter, Vinzenz Särchen, Philipp Zingler, Dieter Adam, Ottmar Janssen, Eberhard Krause, Stefan Schütze
During apoptosis induction by TNF, the extrinsic and intrinsic apoptosis pathways converge at the lysosomal-mitochondrial interface. Earlier studies showed that the lysosomal aspartic protease Cathepsin D (CtsD) cleaves Bid to tBid, resulting in the amplification of the initial apoptotic cascade via mitochondrial outer membrane permeabilization (MOMP).The goal of this study was to identify further targets for CtsD that might be involved in activation upon death receptor ligation. Using a proteomics screen, we identified the heat shock protein 90 (HSP90) to be cleaved by CtsD after stimulation of U937 or other cell lines with TNF, FasL and TRAIL...
October 3, 2016: Oncotarget
Alexandra Rehn, Elisabetta Moroni, Bettina K Zierer, Franziska Tippel, Giulia Morra, Christine John, Klaus Richter, Giorgio Colombo, Johannes Buchner
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone responsible for the activation, maturation, and trafficking of several hundred client proteins in the cell. It is well known that (but not understood how) residues far away from Hsp90's nucleotide binding pocket can regulate its ATPase activity, a phenomenon called allosteric regulation. Here, the computational design of allosteric mutations was combined with in vitro and in vivo experiments to unravel nucleotide-responsive hot spots in the regulation of Hsp90...
September 20, 2016: Journal of Molecular Biology
Sara D Reis, Brígida R Pinho, Jorge M A Oliveira
Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs and suggests different interactions with the cellular proteostasis machinery...
September 22, 2016: Molecular Neurobiology
Annemarie Wolmarans, Brian Lee, Leo Spyracopoulos, Paul LaPointe
Hsp90 is a dimeric molecular chaperone responsible for the folding, maturation, and activation of hundreds of substrate proteins called 'clients'. Numerous co-chaperone proteins regulate progression through the ATP-dependent client activation cycle. The most potent stimulator of the Hsp90 ATPase activity is the co-chaperone Aha1p. Only one molecule of Aha1p is required to fully stimulate the Hsp90 dimer despite the existence of two, presumably identical, binding sites for this regulator. Using ATPase assays with Hsp90 heterodimers, we find that Aha1p stimulates ATPase activity by a three-step mechanism via the catalytic loop in the middle domain of Hsp90...
2016: Scientific Reports
Yi-Jheng Peng, Jing-Jia Huang, Hao-Han Wu, Hsin-Ying Hsieh, Chia-Ying Wu, Shu-Ching Chen, Tsung-Yu Chen, Chih-Yung Tang
Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1...
2016: Scientific Reports
Sascha Röth, Oliver Mirus, Daniela Bublak, Scharf Klaus-Dieter, Enrico Schleiff
HsfB1 is a central regulator of heat stress response and functions dually as transcriptional co-activator of HsfA1a and as general repressor in tomato. HsfB1 is efficiently synthesized during onset of heat stress and rapidly removed in course of attenuation during recovery phase. Initial results point to a complex regime modulating HsfB1 abundance involving the molecular chaperone Hsp90. However, the molecular determinants affecting HsfB1 stability needed to be established. We provide experimental evidence that DNA-bound HsfB1 is efficiently targeted for degradation when active as transcriptional repressor...
August 25, 2016: Plant Journal: for Cell and Molecular Biology
Yoichi Imai, Yoshiro Maru, Junji Tanaka
Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. In addition, studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors exhibit some efficacy in the treatment of acute myelogenous leukemia (AML) with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1...
August 24, 2016: Cancer Science
Su-Wei Xu, Betty Yuen Kwan Law, Simon Wing Fai Mok, Elaine Lai Han Leung, Xing Xing Fan, Paolo Saul Coghi, Wu Zeng, Chung-Hang Leung, Dik-Lung Ma, Liang Liu, Vincent Kam Wai Wong
Drug resistance of non-small cell lung cancer (NSCLC) is highly correlated to the mutation of the epidermal growth factor receptor (EGFR). Although EGFR tyrosine kinase inhibitors (TKIs) are available clinically, the molecular complexity of NSCLC has made it necessary to search for alternative therapeutic approaches to overcome the drug resistance of NSCLC. In the present study, we identified a triterpene molecule derived from the herbal plant Tripterygium wilfordii, celastrol, as a novel autophagy inducer...
October 2016: International Journal of Oncology
José Aguilar-Rodríguez, Beatriz Sabater-Muñoz, Roser Montagud-Martínez, Víctor Berlanga, David Alvarez-Ponce, Andreas Wagner, Mario A Fares
Molecular chaperones, also known as heat-shock proteins, refold misfolded proteins and help other proteins reach their native conformation. Thanks to these abilities, some chaperones, such as the Hsp90 protein or the chaperonin GroEL, can buffer the deleterious phenotypic effects of mutations that alter protein structure and function. Hsp70 chaperones use a chaperoning mechanism different from that of Hsp90 and GroEL, and it is not known whether they can also buffer mutations. Here, we show that they can. To this end, we performed a mutation accumulation experiment in Escherichia coli, followed by whole-genome resequencing...
October 5, 2016: Genome Biology and Evolution
Chaeuk Chung, Geon Yoo, Tackhoon Kim, Dahye Lee, Choong-Sik Lee, Hye Rim Cha, Yeon Hee Park, Jae Young Moon, Sung Soo Jung, Ju Ock Kim, Jae Cheol Lee, Sun Young Kim, Hee Sun Park, Myoungrin Park, Dong Il Park, Dae-Sik Lim, Kang Won Jang, Jeong Eun Lee
Somatic mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is a decisive factor for the therapeutic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma. The stability of mutant EGFR is maintained by various regulators, including heat shock protein 90 (Hsp90). The C terminus of Hsc70-interacting protein (CHIP) is a Hsp70/Hsp90 co-chaperone and exhibits E3 ubiquitin ligase activity. The high-affinity Hsp90-CHIP complex recognizes and selectively regulates their client proteins...
October 14, 2016: Biochemical and Biophysical Research Communications
Kotha Subbaramaiah, Kristy A Brown, Heba Zahid, Gabriel Balmus, Robert S Weiss, Brittney-Shea Herbert, Andrew J Dannenberg
Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of hormone receptor-positive breast cancers. Recently, elevated levels of aromatase, the rate-limiting enzyme for estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90 ATPase activity and aromatase compared with wild-type stromal cells...
July 29, 2016: Journal of Biological Chemistry
Jasmeen Oberoi, Diana M Dunn, Mark R Woodford, Laura Mariotti, Jacqualyn Schulman, Dimitra Bourboulia, Mehdi Mollapour, Cara K Vaughan
The serine/threonine phosphatase protein phosphatase 5 (PP5) regulates hormone- and stress-induced cellular signaling by association with the molecular chaperone heat shock protein 90 (Hsp90). PP5-mediated dephosphorylation of the cochaperone Cdc37 is essential for activation of Hsp90-dependent kinases. However, the details of this mechanism remain unknown. We determined the crystal structure of a Cdc37 phosphomimetic peptide bound to the catalytic domain of PP5. The structure reveals PP5 utilization of conserved elements of phosphoprotein phosphatase (PPP) structure to bind substrate and provides a template for many PPP-substrate interactions...
August 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
Bin Peng, Yi-Jun Gu, Ying Wang, Fan-Fan Cao, Xue Zhang, Deng-Hai Zhang, Jian Hou
Celastrol, a natural compound derived from the Chinese herb Tripterygium wilfordii Hook F, has been proven to inhibit heat shock protein 90 (HSP90) activity and has attracted much attention because of its promising effects in cancer treatment and in ameliorating degenerative neuron diseases. However, the HSP90 structure involved in celastrol interaction is not known. Here, we report a novel celastrol-binding pocket in the HSP90 dimer, predicted by molecular docking. Mutation of the two key binding pocket amino acids (Lys546 and Tyr493) disrupted the binding of celastrol to HSP90 dimers, as detected by isothermal titration calorimetry (ITC)...
July 2016: FEBS Open Bio
Chun Yan Wang, Su Tang Guo, Jia Yu Wang, Xu Guang Yan, Margaret Farrelly, Yuan Yuan Zhang, Fen Liu, Hamed Yari, Ting La, Fu Xi Lei, Lei Jin, Xu Dong Zhang, Chen Chen Jiang
Oncogenic mutations of BRAF occur in approximately 10% of colon cancers and are associated with their resistance to clinically available therapeutic drugs and poor prognosis of the patients. Here we report that colon cancer cells with mutant BRAF are also resistant to the heat shock protein 90 (HSP90) inhibitor AUY922, and that this is caused by rebound activation of ERK and Akt. Although AUY922 triggered rapid reduction in ERK and Akt activation in both wild-type and mutant BRAF colon cancer cells, activation of ERK and Akt rebounded shortly in the latter leading to resistance of the cells to AUY922-induced apoptosis...
July 6, 2016: Oncotarget
D-W Wu, T-C Chen, H-S Huang, H Lee
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show a clinical benefit when used to treat patients with EGFR-mutated non-small-cell lung cancer (NSCLC), but this treatment unfortunately fails in patients with TKI-resistant tumors. We here provide evidence that TC-N19 (N19), a novel dual inhibitor of EGFR and cMET, efficiently overcomes the EGFR-TKI resistance in EGFR-mutated NSCLC cells via simultaneous degradation of both proteins by ubiquitin proteasomes. Comparison with HSP90 inhibitor treatment and knockdown of EGFR and cMET by small hairpin RNAs reveal that the reduction of EGFR and cMET expression by N19 is responsible for overcoming the intrinsic TKI resistance mediated by paxillin (PXN) in high PXN-expressing cells, PXN-overexpressing PC9 cells (PC9-PXN), the EGFR-T790M-mediated TKI resistance in H1975 and CL97 cells, and the acquired resistance to gefitinib in gefitinib-resistant PC9 cells (PC9GR)...
2016: Cell Death & Disease
Patrick R Arsenault, Daisheng Song, Yu Jin Chung, Tejvir S Khurana, Frank S Lee
Prolyl hydroxylase domain protein 2 (PHD2) (also known as EGLN1) is a key oxygen sensor in mammals that posttranslationally modifies hypoxia-inducible factor α (HIF-α) and targets it for degradation. In addition to its catalytic domain, PHD2 contains an evolutionarily conserved zinc finger domain, which we have previously proposed recruits PHD2 to the HSP90 pathway to promote HIF-α hydroxylation. Here, we provide evidence that this recruitment is critical both in vitro and in vivo We show that in vitro, the zinc finger can function as an autonomous recruitment domain to facilitate interaction with HIF-α...
September 15, 2016: Molecular and Cellular Biology
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