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https://www.readbyqxmd.com/read/29791841/functional-genomic-screening-reveals-core-modulators-of-echinocandin-stress-responses-in-candida-albicans
#1
Tavia Caplan, Elizabeth J Polvi, Jinglin L Xie, Shoshana Buckhalter, Michelle D Leach, Nicole Robbins, Leah E Cowen
Candida albicans is a leading cause of death due to fungal infection. Treatment of systemic candidiasis often relies on echinocandins, which disrupt cell wall synthesis. Resistance is readily acquired via mutations in the drug target gene, FKS1. Both basal tolerance and resistance to echinocandins require cellular stress responses. We performed a systematic analysis of 3,030 C. albicans mutants to define circuitry governing cellular responses to echinocandins. We identified 16 genes for which deletion or transcriptional repression enhanced echinocandin susceptibility, including components of the Pkc1-MAPK signaling cascade...
May 22, 2018: Cell Reports
https://www.readbyqxmd.com/read/29774133/sporadic-renal-angiomyolipoma-in-a-patient-with-birt-hogg-dub%C3%A3-chaperones-in-pathogenesis
#2
Rebecca A Sager, Mark R Woodford, Oleg Shapiro, Mehdi Mollapour, Gennady Bratslavsky
Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29758193/inhibition-of-pancreatic-cancer-panc1-cell-migration-by-omeprazole-is-dependent-on-aryl-hydrocarbon-receptor-activation-of-jnk
#3
Un-Ho Jin, Keshav Karki, Sang-Bae Kim, Stephen Safe
Several aryl hydrocarbon receptor (AhR)-active pharmaceuticals were screened as inhibitors of pancreatic cancer cell invasion and identified two compounds, omeprazole, that inhibited invasion. Inhibition of highly invasive Panc1 cell invasion by omeprazole involves an AhR-dependent non-genomic pathway, and omeprazole-mediated inhibition of Panc1 cell invasion was dependent on Jun-N-terminal kinase (JNK) and mitogen-activated kinase kinase 7 (MKK7). The failure of omeprazole to induce nuclear translocation of the AhR was not due to overexpression of cytosolic AhR partner proteins Hsp90 or XAP2, and results of DNA sequencing show that the AhR expressed in Panc1 cells was not mutated...
May 11, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29743242/cyclin-dependent-kinase-7-cdk7-mediated-phosphorylation-of-the-cdk9-activation-loop-promotes-p-tefb-assembly-with-tat-and-proviral-hiv-reactivation
#4
Uri Mbonye, Benlian Wang, Giridharan Gokulrangan, Wuxian Shi, Sichun Yang, Jonathan Karn
The HIV trans-activator Tat recruits the host transcription elongation factor P-TEFb to stimulate proviral transcription. Phosphorylation of Thr186 on the activation loop (T-loop) of cyclin-dependent kinase 9 (CDK9) is essential for its kinase activity and assembly of CDK9 and cyclin T1 (CycT1) to form functional P-TEFb. Phosphorylation of a second highly conserved T-loop site, Ser175, alters the competitive binding of Tat and the host recruitment factor bromodomain containing 4 (BRD4) to P-TEFb. Here, we investigated the intracellular mechanisms that regulate these key phosphorylation events required for HIV transcription...
May 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29725069/hsp90-inhibitors-disrupt-a-transient-hsp90-hsf1-interaction-and-identify-a-noncanonical-model-of-hsp90-mediated-hsf1-regulation
#5
Toshiki Kijima, Thomas L Prince, Megan L Tigue, Kendrick H Yim, Harvey Schwartz, Kristin Beebe, Sunmin Lee, Marek A Budzynski, Heinric Williams, Jane B Trepel, Lea Sistonen, Stuart Calderwood, Len Neckers
Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90...
May 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29725062/hsp90-shapes-protein-and-rna-evolution-to-balance-trade-offs-between-protein-stability-and-aggregation
#6
Ron Geller, Sebastian Pechmann, Ashley Acevedo, Raul Andino, Judith Frydman
Acquisition of mutations is central to evolution; however, the detrimental effects of most mutations on protein folding and stability limit protein evolvability. Molecular chaperones, which suppress aggregation and facilitate polypeptide folding, may alleviate the effects of destabilizing mutations thus promoting sequence diversification. To illuminate how chaperones can influence protein evolution, we examined the effect of reduced activity of the chaperone Hsp90 on poliovirus evolution. We find that Hsp90 offsets evolutionary trade-offs between protein stability and aggregation...
May 3, 2018: Nature Communications
https://www.readbyqxmd.com/read/29721967/the-leber-congenital-amaurosis-linked-protein-aipl1-and-its-critical-role-in-photoreceptors
#7
Almudena Sacristan-Reviriego, Jacqueline van der Spuy
Mutations in the photoreceptor/pineal-expressed gene, aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), are mainly associated with autosomal recessive Leber congenital amaurosis (LCA), the most severe form of inherited retinopathy that occurs in early childhood. AIPL1 functions as a photoreceptor-specific molecular co-chaperone that interacts specifically with the molecular chaperones HSP90 and HSP70 to facilitate the correct folding and assembly of the retinal cGMP phosphodiesterase (PDE6) holoenzyme...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29698859/design-synthesis-and-pharmacological-evaluation-of-alk-and-hsp90-dual-inhibitors-bearing-resorcinol-and-2-4-diaminopyrimidine-motifs
#8
Kaijun Geng, Hongchun Liu, Zilan Song, Chi Zhang, Minmin Zhang, Hong Yang, Jingchen Cao, Meiyu Geng, Aijun Shen, Ao Zhang
Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites...
April 11, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29663854/cyclin-dependent-kinase-1-targeting-improves-sensitivity-to-radiation-in-braf-v600e-colorectal-carcinoma-cells
#9
Girolamo Spagnoletti, Valeria Li Bergolis, Annamaria Piscazzi, Francesca Giannelli, Valentina Condelli, Lorenza Sisinni, Giuseppe Bove, Giovanni Storto, Matteo Landriscina
OBJECTIVES: Preoperative chemoradiation is currently the standard of care in locally advanced rectal carcinoma, even though a subset of rectal tumors does not achieve major clinically meaningful responses upon neoadjuvant chemoradiation. At present, no molecular biomarkers are available to predict response to neoadjuvant chemoradiation and select resistant tumors willing more intense therapeutic strategies. Thus, BRAF mutational status was investigated for its role in favoring resistance to radiation in colorectal carcinoma cell lines and cyclin-dependent kinase 1 as a target to improve radiosensitivity in BRAF V600E colorectal tumor cells...
April 2018: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29662162/a-switch-point-in-the-molecular-chaperone-hsp90-responding-to-client-interaction
#10
Daniel Andreas Rutz, Qi Luo, Lee Freiburger, Tobias Madl, Ville R I Kaila, Michael Sattler, Johannes Buchner
Heat shock protein 90 (Hsp90) is a dimeric molecular chaperone that undergoes large conformational changes during its functional cycle. It has been established that conformational switch points exist in the N-terminal (Hsp90-N) and C-terminal (Hsp90-C) domains of Hsp90, however information for switch points in the large middle-domain (Hsp90-M) is scarce. Here we report on a tryptophan residue in Hsp90-M as a new type of switch point. Our study shows that this conserved tryptophan senses the interaction of Hsp90 with a stringent client protein and transfers this information via a cation-π interaction with a neighboring lysine...
April 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29655319/molecular-dynamics-simulations-of-site-point-mutations-in-the-tpr-domain-of-cyclophilin-40-identify-conformational-states-with-distinct-dynamic-and-enzymatic-properties
#11
Mert Gur, Elizabeth A Blackburn, Jia Ning, Vikram Narayan, Kathryn L Ball, Malcolm D Walkinshaw, Burak Erman
Cyclophilin 40 (Cyp40) is a member of the immunophilin family that acts as a peptidyl-prolyl-isomerase enzyme and binds to the heat shock protein 90 (Hsp90). Its structure comprises an N-terminal cyclophilin domain and a C-terminal tetratricopeptide (TPR) domain. Cyp40 is overexpressed in prostate cancer and certain T-cell lymphomas. The groove for Hsp90 binding on the TPR domain includes residues Lys227 and Lys308, referred to as the carboxylate clamp, and is essential for Cyp40-Hsp90 binding. In this study, the effect of two mutations, K227A and K308A, and their combinative mutant was investigated by performing a total of 5...
April 14, 2018: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29626131/pervasive-contingency-and-entrenchment-in-a-billion-years-of-hsp90-evolution
#12
Tyler N Starr, Julia M Flynn, Parul Mishra, Daniel N A Bolon, Joseph W Thornton
Interactions among mutations within a protein have the potential to make molecular evolution contingent and irreversible, but the extent to which epistasis actually shaped historical evolutionary trajectories is unclear. To address this question, we experimentally measured how the fitness effects of historical sequence substitutions changed during the billion-year evolutionary history of the heat shock protein 90 (Hsp90) ATPase domain beginning from a deep eukaryotic ancestor to modern Saccharomyces cerevisiae We found a pervasive influence of epistasis...
April 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29587629/comparative-analysis-of-fkbp-family-protein-evaluation-structure-and-function-in-mammals-and-drosophila-melanogaster
#13
REVIEW
George Ghartey-Kwansah, Zhongguang Li, Rui Feng, Liyang Wang, Xin Zhou, Frederic Z Chen, Meng Meng Xu, Odell Jones, Yulian Mu, Shawn Chen, Joseph Bryant, Williams B Isaacs, Jianjie Ma, Xuehong Xu
BACKGROUND: FK506-binding proteins (FKBPs) have become the subject of considerable interest in several fields, leading to the identification of several cellular and molecular pathways in which FKBPs impact prenatal development and pathogenesis of many human diseases. MAIN BODY: This analysis revealed differences between how mammalian and Drosophila FKBPs mechanisms function in relation to the immunosuppressant drugs, FK506 and rapamycin. Differences that could be used to design insect-specific pesticides...
March 27, 2018: BMC Developmental Biology
https://www.readbyqxmd.com/read/29529211/activity-of-hsp90-inhibiton-in-a-metastatic-lung-cancer-patient-with-a-germline-brca1-mutation
#14
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
https://www.readbyqxmd.com/read/29517411/chaperone-complex-formation-of-the-transcription-factor-malr-involved-in-maltose-utilization-and-amylolytic-enzyme-production-in-aspergillus-oryzae
#15
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
https://www.readbyqxmd.com/read/29507057/the-molecular-chaperone-hsp90-promotes-notch-signaling-in-the-germline-of-caenorhabditis-elegans
#16
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...
May 4, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29481571/17-aag-inhibits-vemurafenib-associated-map-kinase-activation-and-is-synergistic-with-cellular-immunotherapy-in-a-murine-melanoma-model
#17
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
https://www.readbyqxmd.com/read/29478821/disease-variants-of-fgfr3-reveal-molecular-basis-for-the-recognition-and-additional-roles-for-cdc37-in-hsp90-chaperone-system
#18
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...
March 6, 2018: Structure
https://www.readbyqxmd.com/read/29471895/etv6-flt3-fusion-is-a-novel-client-protein-of-hsp90
#19
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
https://www.readbyqxmd.com/read/29402077/trifunctional-high-throughput-screen-identifies-promising-scaffold-to-inhibit-grp94-and-treat-myocilin-associated-glaucoma
#20
Dustin J E 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 hasten 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...
April 20, 2018: ACS Chemical Biology
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