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https://www.readbyqxmd.com/read/28522750/inhibition-of-mitochondrial-matrix-chaperones-and-anti-apoptotic-bcl-2-family-proteins-empower-antitumor-therapeutic-responses
#1
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Dario C Altieri, Markus D Siegelin
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28522336/geldanamycin-inhibits-fas-signaling-pathway-and-protects-neurons-against-ischemia
#2
Xiao-Hui Yin, Yan-Ling Han, Ying Zhuang, Jing-Zhi Yan, Chong Li
The inhibitor of Heat shock proteins 90, geldanamycin (GA), has been reported neuroprotective against both global and focal brain ischemia. To understand the mechanisms underlies the neuroprotection effect of GA, we investigated the relationship between GA pretreatment and Fas signaling pathway in rat global brain ischemia/reperfusion model in the present study. Results showed that GA attenuated neuron loss significantly in hippocampal CA1 region. Upon GA pretreatment, Mixed Lineage Kinase 3 (MLK3) expression and activation and FasL expression was decreased, the assembly of death-inducing signaling complex and activation of downstream apoptosis-associating proteins were inhibited along with neuroprotection...
May 15, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28515311/control-of-hsp90-chaperone-and-its-clients-by-n-terminal-acetylation-and-the-n-end-rule-pathway
#3
Jang-Hyun Oh, Ju-Yeon Hyun, Alexander Varshavsky
We found that the heat shock protein 90 (Hsp90) chaperone system of the yeast Saccharomyces cerevisiae is greatly impaired in naa10Δ cells, which lack the NatA N(α)-terminal acetylase (Nt-acetylase) and therefore cannot N-terminally acetylate a majority of normally N-terminally acetylated proteins, including Hsp90 and most of its cochaperones. Chk1, a mitotic checkpoint kinase and a client of Hsp90, was degraded relatively slowly in wild-type cells but was rapidly destroyed in naa10Δ cells by the Arg/N-end rule pathway, which recognized a C terminus-proximal degron of Chk1...
May 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28515276/assembly-of-the-u5-snrnp-component-prpf8-is-controlled-by-the-hsp90-r2tp-chaperones
#4
Anna Malinová, Zuzana Cvačková, Daniel Matějů, Zuzana Hořejší, Claire Abéza, Franck Vandermoere, Edouard Bertrand, David Staněk, Céline Verheggen
Splicing is catalyzed by the spliceosome, a complex of five major small nuclear ribonucleoprotein particles (snRNPs). The pre-mRNA splicing factor PRPF8 is a crucial component of the U5 snRNP, and together with EFTUD2 and SNRNP200, it forms a central module of the spliceosome. Using quantitative proteomics, we identified assembly intermediates containing PRPF8, EFTUD2, and SNRNP200 in association with the HSP90/R2TP complex, its ZNHIT2 cofactor, and additional proteins. HSP90 and R2TP bind unassembled U5 proteins in the cytoplasm, stabilize them, and promote the formation of the U5 snRNP...
May 17, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28512265/chaetocin-enhances-dendritic-cell-function-via-the-induction-of-heat-shock-protein-and-cancer-testis-antigens-in-myeloma-cells
#5
Manh-Cuong Vo, Thanh-Nhan Nguyen-Pham, Hyun-Ju Lee, Sung-Hoon Jung, Nu-Ri Choi, My-Dung Hoang, Hyeoung-Joon Kim, Je-Jung Lee
Dendritic cells (DC)-based vaccines are considered useful in cancer immuno-therapy, and the interactions of DC and dying tumor cells are important and promising for cancer immunotherapy. We investigated whether chaetocin could be used to induce death of myeloma cells, for loading onto DCs can affect DCs function. In this study, we show that the dying myeloma cells treated with chaetocin resulted in the induction of heat shock protein (HSP) 90, which was inhibited by antioxidant N-acetyl cysteine, and showed an increase in the expression of MAGE-A3 and MAGE-C1/CT7...
April 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28510050/a-review-of-multi-domain-and-flexible-molecular-chaperones-studies-by-small-angle-x-ray-scattering
#6
REVIEW
Júlio C Borges, Thiago V Seraphim, Paulo R Dores-Silva, Leandro R S Barbosa
Intrinsic flexibility is closely related to protein function, and a plethora of important regulatory proteins have been found to be flexible, multi-domain or even intrinsically disordered. On the one hand, understanding such systems depends on how these proteins behave in solution. On the other, small-angle X-ray scattering (SAXS) is a technique that fulfills the requirements to study protein structure and dynamics relatively quickly with few experimental limitations. Molecular chaperones from Hsp70 and Hsp90 families are multi-domain proteins containing flexible and/or disordered regions that play central roles in cellular proteostasis...
June 2016: Biophysical Reviews
https://www.readbyqxmd.com/read/28505025/a-rodent-model-of-cardiac-donation-after-circulatory-death-and-novel-biomarkers-of-cardiac-viability-during-ex-vivo-heart-perfusion
#7
Mark J Kearns, Sally Miller, Anson Cheung, Jamil Bashir, Stephanie Wong, Michael A Seidman, John H Boyd
BACKGROUND: Organ donation after circulatory death (DCD) is increasingly being used as a means of addressing the organ supply/demand mismatch in solid organ transplantation. There is reluctance to use DCD hearts, due to an inability to precisely identify hearts that have suffered irreversible injury. We investigated novel biomarkers and clinically relevant endpoints across a spectrum of warm ischemic times (WITs), prior to and during ex vivo heart perfusion (EVHP), to identify features associated with a non-viable cardiac phenotype...
May 13, 2017: Transplantation
https://www.readbyqxmd.com/read/28504714/cytoplasmic-translocation-of-mta1-coregulator-promotes-de-repression-of-sgk1-transcription-in-hypoxic-cancer-cells
#8
H Marzook, S Deivendran, B George, G Reshmi, T R Santhoshkumar, R Kumar, M R Pillai
Chromatin remodeling factor metastatic tumor protein 1 (MTA1), one of the most upregulated oncogene in human cancer, has an important role in gene expression, cell survival and promoting hypoxic response. Successful cancer progression is dependent on the ability of cells to utilize its survival pathways for adapting to hypoxic microenvironment. Although MTA1 is a stress-responsive gene, but whether hypoxia modulates its function and its role in engaging other core stress-responsive survival pathway(s) remains unknown...
May 15, 2017: Oncogene
https://www.readbyqxmd.com/read/28504248/the-flavonoid-tl-2-8-induces-cell-death-and-immature-mitophagy-in-breast-cancer-cells-via-abrogating-the-function-of-the-aha1-hsp90-complex
#9
Hui-Juan Liu, Xiao-Xiao Jiang, Yi-Zhen Guo, Fang-Hui Sun, Xin-Hui Kou, Yong Bao, Zhu-Qing Zhang, Zhao-Hu Lin, Ting-Bo Ding, Lan Jiang, Xin-Sheng Lei, Yong-Hua Yang
The flavonoid quercetin exhibits significant anticancer activities with few side effects. In the current study, we characterized TL-2-8, a quercetin derivative, as a novel anticancer agent in vitro and in vivo. Cell proliferation and viability were assessed using Cell Counting Kit-8 and CellTiter-Blue assay, respectively. Cell death was examined using PI staining or a TUNEL assay. Mitophagy was determined by measuring autophagic flux and by confocal imaging. Protein expression was examined by Western blotting...
May 1, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28500970/histopathological-changes-and-lipid-metabolism-in-the-liver-of-bufo-gargarizans-tadpoles-exposed-to-triclosan
#10
Lihong Chai, Aixia Chen, Pingping Luo, Hongfeng Zhao, Hongyuan Wang
In the current study, the adverse effects of TCS on liver health of B. gargarizans tadpoles were assessed. B. gargarizans larvae were exposed to TCS at 0, 10, 30, 60, and 150 μg L(-1) from Gosner stage 3 until metamorphic climax. The hepatosomatic index (HSI), hepatic histological and ultrastructural features, and transcript levels of genes associated with detoxification and oxidative stress as well as lipid metabolism in the livers were determined. Exposure to 150 μg L(-1) TCS resulted in increased HSI of tadpoles at metamorphic climax...
May 7, 2017: Chemosphere
https://www.readbyqxmd.com/read/28499253/the-role-of-sodium-hydrosulfide-in-attenuating-the-aging-process-via-pi3k-akt-and-camkk%C3%AE-ampk-pathways
#11
Xubo Chen, Xueyan Zhao, Hua Cai, Haiying Sun, Yujuan Hu, Xiang Huang, Wen Kong, Weijia Kong
Age-related dysfunction of the central auditory system, known as central presbycusis, is characterized by defects in speech perception and sound localization. It is important to determine the pathogenesis of central presbycusis in order to explore a feasible and effective intervention method. Recent work has provided fascinating insight into the beneficial function of H2S on oxidative stress and stress-related disease. In this study, we investigated the pathogenesis of central presbycusis and tried to explore the mechanism of H2S action on different aspects of aging by utilizing a mimetic aging rat and senescent cellular model...
April 25, 2017: Redox Biology
https://www.readbyqxmd.com/read/28497897/expression-profile-of-heat-shock-proteins-in-placental-tissues-of-patients-with-preterm-prelabor-rupture-of-membranes-and-spontaneous-preterm-labor-with-intact-membranes
#12
Lenka Dvorakova, Katarina Ivankova, Ladislav Krofta, Ilona Hromadnikova
PROBLEM: Investigating the stress response in the central cotyledon zone of placental tissue in pregnancies with PPROM, PTB, and at term in labor. METHOD OF STUDY: Gene expression of Hsp27, Hsp60, Hsp70, Hsp90, and HspBP1 was compared between these particular groups. Correlation between variables including Hsp gene expression in placental tissue and the gestational age at delivery, WBC count at admission, and serum levels of CRP at admission in patients with PPROM and PTB was determined...
May 12, 2017: American Journal of Reproductive Immunology: AJRI
https://www.readbyqxmd.com/read/28496161/bacterial-physiology-hsp90-is-the-hot-guy-for-shewanella-oneidensis
#13
Irene Vacca
No abstract text is available yet for this article.
May 12, 2017: Nature Reviews. Microbiology
https://www.readbyqxmd.com/read/28495509/cloning-of-three-heat-shock-protein-genes-hsp70-hsp90%C3%AE-and-hsp90%C3%AE-and-their-expressions-in-response-to-thermal-stress-in-loach-misgurnus-anguillicaudatus-fed-with-different-levels-of-vitamin-c
#14
Jie Yan, Xiao Liang, Yin Zhang, Yang Li, Xiaojuan Cao, Jian Gao
Heat shock protein 70 (HSP70) and 90 (HSP90) are the most broadly studied proteins in HSP families. They play key roles in cells as molecular chaperones, in response to stress conditions such as thermal stress. In this study, full-length cDNA sequences of HSP70, HSP90α and HSP90β from loach Misgurnus anguillicaudatus were cloned. The full-length cDNA of HSP70 in loach was 2332bp encoding 644 amino acids, while HSP90α and HSP90β were 2586bp and 2678bp in length, encoding 729 and 727 amino acids, respectively...
May 8, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28495207/targeting-the-hsp90-c-terminal-domain-to-induce-allosteric-inhibition-and-selective-client-downregulation
#15
Kourtney M Goode, Dino Petrov, Renee E Vickman, Scott A Crist, Pete E Pascuzzi, Tim L Ratliff, V Jo Davisson, Tony R Hazbun
BACKGROUND: Inhibition of Hsp90 is desirable due to potential downregulation of oncogenic clients. Early generation inhibitors bind to the N-terminal domain (NTD) but C-terminal domain (CTD) inhibitors are a promising class because they do not induce a heat shock response. Here we present a new structural class of CTD binding molecules with a unique allosteric inhibition mechanism. METHODS: A hit molecule, NSC145366, and structurally similar probes were assessed for inhibition of Hsp90 activities...
May 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28493081/regulation-of-inos-derived-ros-generation-by-hsp90-and-cav-1-in-porcine-reproductive-and-respiratory-syndrome-virus-infected-swine-lung-injury
#16
Meiping Yan, Make Hou, Jie Liu, Songlin Zhang, Bang Liu, Xiaoxiong Wu, Guoquan Liu
In the lungs, endothelial nitric oxide synthase (eNOS) is usually expressed in endothelial cells and inducible nitric oxide synthase (iNOS) is mainly expressed in alveolar macrophages and epithelial cells. Both eNOS and iNOS are involved in lung inflammation. While they play several roles in lung inflammation formation and resolution, their expression and activity are also regulated by inflammatory factors. Their expression relationship in virus infection-induced lung injury is not well addressed. In this report, we analyzed expression of both eNOS and iNOS, the production of nitric oxide (NO) and reactive oxygen species (ROS), and expression of their associated regulatory proteins, heat shock protein 90 (HSP90) and caveolin-1 (Cav-1), in a swine lung injury model induced by porcine reproductive and respiratory syndrome virus (PRRSV) infection...
May 10, 2017: Inflammation
https://www.readbyqxmd.com/read/28484020/hsp104-disaggregase-at-normal-levels-cures-many-psi-prion-variants-in-a-process-promoted-by-sti1p-hsp90-and-sis1p
#17
Anton Gorkovskiy, Michael Reidy, Daniel C Masison, Reed B Wickner
Overproduction or deficiency of many chaperones and other cellular components cure the yeast prions [PSI(+)] (formed by Sup35p) or [URE3] (based on Ure2p). However, at normal expression levels, Btn2p and Cur1p eliminate most newly arising [URE3] variants but do not cure [PSI(+)], even after overexpression. Deficiency or overproduction of Hsp104 cures the [PSI(+)] prion. Hsp104 deficiency curing is a result of failure to cleave the Sup35p amyloid filaments to make new seeds, whereas Hsp104 overproduction curing occurs by a different mechanism...
May 8, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28483634/protein-mediated-regulation-of-the-nhe1-isoform-of-the-na-h-exchanger-in-renal-cells-a-regulatory-role-of-hsp90-and-akt-kinase
#18
Ayodeji Odunewu-Aderibigbe, Larry Fliegel
Na(+)/H(+) exchanger isoform one (NHE1) is a pH regulatory protein that is present in renal tissues and serves to remove protons from within cells and protect against intracellular acidification. NHE1 has a large 315 amino acid cytosolic regulatory domain that regulates the catalytic membrane domain. We examined protein-mediated regulation of NHE1 through the cytosolic domain. Affinity chromatography with the C-terminus of NHE1 yielded a number of NHE1 binding proteins including 14-3-3 protein, heat shock proteins (Hsp90 and Hsp70) and Na(+)/K(+) ATPase...
May 5, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28482755/3d-qsar-molecular-docking-and-molecular-dynamic-simulations-to-prediction-of-new-hsp90-inhibitors-based-on-isoxazole-scaffold
#19
Maryam Abbasi, Seyed Ahmad Emami, Massoud Amanlou
Heat shock protein 90(Hsp90), as a molecular chaperone, play a crucial role in folding and proper function of many proteins. Hsp90 inhibitors containing isoxazole scaffold are currently being used in the treatment of cancer as tumor suppressers. Here in the present studies, new compounds based on isoxazole scaffold were predicted using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamic (MD) simulations...
May 9, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28482218/structure-based-virtual-screening-and-optimization-of-modulators-targeting-hsp90-cdc37-interaction
#20
Lei Wang, Li Li, Zi-Han Zhou, Zheng-Yu Jiang, Qi-Dong You, Xiao-Li Xu
Identification of novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 protein-protein interaction (PPI) could be an alternative strategy to achieve Hsp90 inhibition. In this paper, a series of small molecules targeting Hsp90-Cdc37 complex are addressed and characterized. The molecules' key characters are determined by utilizing a structure-based virtual screening workflow, derivatives synthesis, and biological evaluation. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on the virtual hit of VS-8 with potent activity, which resulted in the discovery of compound 10 as a more potent regulator of Hsp90-Cdc37 interaction with a promising inhibitory effect (IC50 = 27 μM), a moderate binding capacity (KD = 40 μM) and a preferable antiproliferative activity against several cancer lines including MCF-7, SKBR3 and A549 cell lines (IC50 = 26 μM, 15 μM and 38 μM respectively)...
April 30, 2017: European Journal of Medicinal Chemistry
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