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Patrick R Arsenault, Daisheng Song, Marian Bergkamp, Andrew M Ravaschiere, Bradleigh E Navalsky, Paul M Lieberman, Frank S Lee
The Prolyl Hydroxylase Domain protein (PHD):Hypoxia Inducible Factor (HIF) pathway is the main pathway by which changes in oxygen concentration are transduced to changes in gene expression. In mammals, there are three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such as ERYTHROPOIETIN (EPO), which controls red cell mass and hematocrit. PHD2 is distinctive among the three PHDs in that it contains an N-terminal MYND type zinc finger. We have proposed that this zinc finger binds a Pro-Xaa-Leu-Glu (PXLE) motif found in proteins of the HSP90 pathway to facilitate HIF-α hydroxylation...
October 22, 2016: Chembiochem: a European Journal of Chemical Biology
Ju Hui Jeong, Yong Jin Oh, Taeg Kyu Kwon, Young Ho Seo
The molecular chaperone Hsp90 has emerged as an attractive cancer therapeutic target due to its role in cellular homeostasis by modulating the stabilization and maturation of many oncogenic proteins. In this study, we designed and synthesized a series of Hsp90 inhibitors that hybridized NVP-AUY992 (2) and PU3 (3) in the chalcone scaffold using a structure-based approach. Our results indicate that compound 1g inhibited the proliferation of gefitinib-resistant non-small cell lung cancer (H1975) cells, downregulated the expression of client proteins of Hsp90 including EGFR, MET, Her2 and Akt, and up-regulated the expression of Hsp70...
October 21, 2016: Archives of Pharmacal Research
Greg Hodge, Eugene Roscioli, Hubertus Jersmann, Hai B Tran, Mark Holmes, Paul N Reynolds, Sandra Hodge
BACKGROUND: Corticosteroid resistance is a major barrier to effective treatment of COPD. We have shown that the resistance is associated with decreased expression of glucocorticoid receptor (GCR) by senescent CD28nullCD8+ pro-inflammatory lymphocytes in peripheral blood of COPD patients. GCR must be bound to molecular chaperones heat shock proteins (Hsp) 70 and Hsp90 to acquire a high-affinity steroid binding conformation, and traffic to the nucleus. We hypothesized a loss of Hsp70/90 from these lymphocytes may further contribute to steroid resistance in COPD...
October 21, 2016: Respiratory Research
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
Xiaoli Xu, Yue Wu, Mingyang Hu, Xiang Li, Qichao Bao, Jinlei Bian, Qidong You, Xiaojin Zhang
DDO-6101, a simplified structure obtained from the Garcinia natural product (NP) gambogic acid (GA), has been previously shown to possess high cytotoxicity to a variety of human tumour cell lines. To improve its physicochemical properties and in vivo cytotoxic potency, a series of novel carbamate-bearing derivatives based on DDO-6101 was synthesized and characterized. The structural modifications revealed that the presence of a carbamate moiety was useful for obtaining comparable cytotoxicity and improved aqueous solubility and permeability...
October 21, 2016: Scientific Reports
Rosa Pennisi, Paolo Ascenzi, Alessandra di Masi
October 18, 2016: Biomolecules
Yvonne Schaletzki, Marie-Luise Kromrey, Susanne Bröderdorf, Elke Hammer, Markus Grube, Paul Hagen, Sonja Sucic, Michael Freissmuth, Uwe Völker, Andreas Greinacher, Bernhard H Rauch, Heyo K Kroemer, Gabriele Jedlitschky
The multidrug resistance protein 4 (MRP4/ABCC4) has been identified as an important transporter for signalling molecules including cyclic nucleotides and several lipid mediators in platelets and may thus represent a novel target to interfere with platelet function. Besides its localisation in the plasma membrane, MRP4 has been also detected in the membrane of dense granules in resting platelets. In polarised cells it is localised at the basolateral or apical plasma membrane. To date, the mechanism of MRP4 trafficking has not been elucidated; protein interactions may regulate both the localisation and function of this transporter...
October 20, 2016: Thrombosis and Haemostasis
Xiaokui Gu, Wei Xue, Yajing Yin, Hongwei Liu, Shaojie Li, Xianyun Sun
Heat Shock Protein 90 (Hsp90) is essential for tumor progression in humans and drug resistance in fungi. However, the roles of its many co-chaperones in antifungal resistance are unknown. In this study, by susceptibility test of Neurospora crassa mutants lacking each of 18 Hsp90/Calcineurin system member genes (including 8 Hsp90 co-chaperone genes) to antifungal drugs and other stresses, we demonstrate that the Hsp90 co-chaperones Sti1 (Hop1 in yeast), Aha1, and P23 (Sba1 in yeast) were required for the basal resistance to antifungal azoles and heat stress...
2016: Frontiers in Microbiology
Stefan Tukaj, Anna Görög, Konrad Kleszczyński, Detlef Zillikens, Sarolta Kárpáti, Michael Kasperkiewicz
Inflammation-induced heat shock proteins (HSPs) and hypovitaminosis D have been reported to impact immune responses and to be associated with autoimmune diseases including celiac disease (CD), a gluten-sensitive enteropathy mediated by autoantibodies against tissue transglutaminase (TG2). Recently, we provided evidence for a role of autoantibodies to HSPs in patients with dermatitis herpetiformis (DH), an inflammatory skin disease induced by underlying latent CD. In this study, we aimed at investigating the humoral autoimmune response to HSPs and vitamin D status in CD patients (n=15) presenting without the cutaneous disease manifestation...
October 16, 2016: Journal of Steroid Biochemistry and Molecular Biology
Marie-Julie Nokin, Florence Durieux, Paul Peixoto, Barbara Chiavarina, Olivier Peulen, Arnaud Blomme, Andrei Turtoi, Brunella Costanza, Nicolas Smargiasso, Dominique Baiwir, Jean L Scheijen, Casper G Schalkwijk, Justine Leenders, Pascal De Tullio, Elettra Bianchi, Marc Thiry, Koji Uchida, David A Spiegel, James R Cochrane, Craig A Hutton, Edwin De Pauw, Philippe Delvenne, Dominique Belpomme, Vincent Castronovo, Akeila Bellahcène
Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion...
October 19, 2016: ELife
Schammim Ray Amith, Krista Marie Vincent, Jodi Marie Wilkinson, Lynne Marie Postovit, Larry Fliegel
Mounting evidence supports a major role for the Na(+)/H(+) exchanger NHE1 in cancer progression and metastasis. NHE1 is hyperactive at the onset of oncogenic transformation, resulting in intracellular alkalinization and extracellular microenvironmental acidification. These conditions promote invasion and facilitate metastasis. However, the signal pathways governing the regulation of exchanger activity are still unclear. This is especially important in the aggressively metastatic, triple-negative basal breast cancer subtype...
October 15, 2016: Cellular Signalling
Ho Shin Kim, Mannkyu Hong, Jihyae Ann, Suyoung Yoon, Cong-Truong Nguyen, Su-Chan Lee, Ho-Young Lee, Young-Ger Suh, Ji Hae Seo, Hoon Choi, Jun Yong Kim, Kyu-Won Kim, Joohwan Kim, Young-Myeong Kim, So-Jung Park, Hyun-Ju Park, Jeewoo Lee
Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure-activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80...
September 30, 2016: Bioorganic & Medicinal Chemistry
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
Francesca Lupo, Elena Tibaldi, Alessandro Matte, Alok K Sharma, Anna Maria Brunati, Seth L Alper, Carlo Zancanaro, Donatella Benati, Angela Siciliano, Mariarita Bertoldi, Francesca Zonti, Alexander Storch, Ruth H Walker, Adrian Danek, Benedikt Bader, Andreas Hermann, Lucia De Franceschi
Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a protein of unknown function. We report here for the first time that chorea-acanthocytosis red-cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1, Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation...
October 14, 2016: Blood
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
Simona Panella, Maria Elena Marcocci, Ignacio Celestino, Sergio Valente, Clemens Zwergel, Domenica Donatella Li Puma, Lucia Nencioni, Antonello Mai, Anna Teresa Palamara, Giovanna Simonetti
AIM: Histone deacetylases (HDACs) regulate the life-cycle of several viruses. We investigated the ability of different HDAC-inhibitors, to interfere with influenza virus A/Puerto Rico/8/34/H1N1 (PR8 virus) replication in Madin-Darby canine kidney and NCI cells. RESULTS: 3-(5-(3-Fluorophenyl)-3-oxoprop-1-en-1-yl)-1-methyl-1H-pyrrol-2-yl)-N-hydroxyacrylamide (MC1568) inhibited HDAC6/8 activity and PR8 virus replication, with decreased expression of viral proteins and their mRNAs...
October 14, 2016: Future Medicinal Chemistry
Andreas Schneider, Michael Blatzer, Wilfried Posch, Ralf Schubert, Cornelia Lass-Flörl, Stanislaw Schmidt, Thomas Lehrnbecher
Natural Killer (NK) cells are active against Aspergillus fumigatus, which in turn is able to impair the host defense. Unfortunately, little is known on the mutual interaction of NK cells and A. fumigatus. We coincubated human NK cells with A. fumigatus hyphae and assessed the gene expression and protein concentration of selected molecules. We found that A. fumigatus up-regulates the gene expression of pro-inflammatory molecules in NK cells, but inhibited the release of these molecules resulting in intracellular accumulation and limited extracellular availability...
October 12, 2016: Oncotarget
Ameer L Elaimy, Aarif Ahsan, Katherine Marsh, William B Pratt, Dipankar Ray, Theodore S Lawrence, Mukesh K Nyati
Heat shock protein 90 is a chaperone that plays an essential role in the stabilization of a large number of signal transduction molecules, many of which are associated with oncogenesis. An Hsp90 isoform (Hsp90α) has been shown to be selectively phosphorylated on two N-terminal threonine residues (threonine 5 and 7) and is involved in the DNA damage response and apoptosis. However, the kinase that phosphorylates Hsp90α after ionizing radiation (IR) and its role in post-radiation DNA repair remains unclear...
October 11, 2016: Oncotarget
Amanda R Dancsok, Karama Asleh-Aburaya, Torsten O Nielsen
The heterogeneity of sarcomas with regard to molecular genesis, histology, clinical characteristics, and response to treatment makes management of these rare yet diverse neoplasms particularly challenging. This review encompasses recent developments in sarcoma diagnostics and treatment, including cytotoxic, targeted, epigenetic, and immune therapy agents. In the past year, groups internationally explored the impact of adding mandatory molecular testing to histological diagnosis, reporting some changes in diagnosis and/or management; however, the impact on outcomes could not be adequately assessed...
October 9, 2016: Oncotarget
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