scholarly journals An HSP90-regulated reduced-eye phenotype in Tribolium shows fitness benefits and thus provides evidence for evolutionary capacitance

2019 ◽  
Author(s):  
Rasha Aboelsoud ◽  
Joachim Kurtz
Keyword(s):  
Genetic Variation ◽  
Light Stress ◽  
Heat Shock Protein 90 ◽  
Raw Material ◽  
Ambient Light ◽  
Rapid Adaptation ◽  
Hsp90 Inhibition ◽  
Fitness Benefits ◽  
Chemical Inhibition ◽  
Evolutionary Capacitance

AbstractEvolution relies on genetic variation as the raw material for adaptation. The release of cryptic genetic variation (CGV), which can be regulated by the evolutionary capacitor heat shock protein 90 (HSP90), may thus be important for rapid adaptation. However, the fitness benefits of HSP90-regulated phenotypes are still under debate. Here, we show in the important model insect Tribolium castaneum that HSP90 impairment by two independent methods, RNA interference and chemical inhibition, revealed the same reduced-eye phenotype, which was stably inherited without further HSP90 inhibition. The penetrance and fitness of this trait increased under ambient light stress. This is the first demonstration that a phenotype released through HSP90 inhibition can be adaptive.

2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition

2016 ◽  
Vol 14 (2) ◽  
pp. 716-723 ◽  
Author(s):  
Kunal Nepali ◽  
Sunil Kumar ◽  
Hsiang-Ling Huang ◽  
Fei-Chiao Kuo ◽  
Cheng-Hsin Lee ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Anticancer Agents ◽  
Heat Shock Protein 90 ◽  
Scaffold Hopping ◽  
Hsp90 Inhibition

This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11–23) on the basis of scaffold hopping.

Effect of heat-shock protein-90 (HSP90) inhibition on human hepatocytes and on liver regeneration in experimental models

Surgery ◽  
2010 ◽  
Vol 147 (5) ◽  
pp. 704-712 ◽  
Author(s):  
Christina Hackl ◽  
Akira Mori ◽  
Christian Moser ◽  
Sven A. Lang ◽  
Rania Dayoub ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Liver Regeneration ◽  
Heat Shock Protein 90 ◽  
Experimental Models ◽  
Human Hepatocytes ◽  
Hsp90 Inhibition

scholarly journals Standing Genetic Variation in Contingency Loci Drives the Rapid Adaptation of Campylobacter jejuni to a Novel Host

PLoS ONE ◽  
2011 ◽  
Vol 6 (1) ◽  
pp. e16399 ◽  
Author(s):  
John P. Jerome ◽  
Julia A. Bell ◽  
Anne E. Plovanich-Jones ◽  
Jeffrey E. Barrick ◽  
C. Titus Brown ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Campylobacter Jejuni ◽  
Rapid Adaptation ◽  
Novel Host ◽  
Contingency Loci

scholarly journals HSP90 is a chaperone for DLK and is required for axon injury signaling

2018 ◽  
Vol 115 (42) ◽  
pp. E9899-E9908 ◽  
Author(s):  
Scott Karney-Grobe ◽  
Alexandra Russo ◽  
Erin Frey ◽  
Jeffrey Milbrandt ◽  
Aaron DiAntonio
Keyword(s):  
Leucine Zipper ◽  
Axon Regeneration ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Loss Of Function ◽  
Hsp90 Inhibition ◽  
Axon Injury ◽  
Evolutionarily Conserved ◽  
The Stability

Peripheral nerve injury induces a robust proregenerative program that drives axon regeneration. While many regeneration-associated genes are known, the mechanisms by which injury activates them are less well-understood. To identify such mechanisms, we performed a loss-of-function pharmacological screen in cultured adult mouse sensory neurons for proteins required to activate this program. Well-characterized inhibitors were present as injury signaling was induced but were removed before axon outgrowth to identify molecules that block induction of the program. Of 480 compounds, 35 prevented injury-induced neurite regrowth. The top hits were inhibitors to heat shock protein 90 (HSP90), a chaperone with no known role in axon injury. HSP90 inhibition blocks injury-induced activation of the proregenerative transcription factor cJun and several regeneration-associated genes. These phenotypes mimic loss of the proregenerative kinase, dual leucine zipper kinase (DLK), a critical neuronal stress sensor that drives axon degeneration, axon regeneration, and cell death. HSP90 is an atypical chaperone that promotes the stability of signaling molecules. HSP90 and DLK show two hallmarks of HSP90–client relationships: (i) HSP90 binds DLK, and (ii) HSP90 inhibition leads to rapid degradation of existing DLK protein. Moreover, HSP90 is required for DLK stability in vivo, where HSP90 inhibitor reduces DLK protein in the sciatic nerve. This phenomenon is evolutionarily conserved in Drosophila. Genetic knockdown of Drosophila HSP90, Hsp83, decreases levels of Drosophila DLK, Wallenda, and blocks Wallenda-dependent synaptic terminal overgrowth and injury signaling. Our findings support the hypothesis that HSP90 chaperones DLK and is required for DLK functions, including proregenerative axon injury signaling.

scholarly journals Correction: 2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition

2018 ◽  
Vol 16 (25) ◽  
pp. 4734-4734
Author(s):  
Kunal Nepali ◽  
Sunil Kumar ◽  
Hsiang-Ling Huang ◽  
Fei-Chiao Kuo ◽  
Cheng-Hsin Lee ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Anticancer Agents ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibition

Correction for ‘2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition’ by Kunal Nepali et al., Org. Biomol. Chem., 2016, 14, 716–723.

Inhibition and flare patterns of metabolic response to the heat shock protein 90 (Hsp90) inhibitor IPI-504 visualized by FDG-PET in patients (pts) with advanced gastrointestinal stromal tumors (GIST) resistant to tyrosine kinase inhibitor (TKI) therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3530-3530 ◽  
Author(s):  
A. D. Van den Abbeele ◽  
J. T. Yap ◽  
D. S. Grayzel ◽  
J. Walker ◽  
G. D. Demetri
Keyword(s):  
Fdg Pet ◽  
Kinase Inhibitor ◽  
Metabolic Response ◽  
Clinical Investigation ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Resistance Mutations ◽  
Hsp90 Inhibition ◽  
Standardized Uptake Values ◽  
Time Point

3530 Background: We have previously demonstrated the inhibition and rebound of GIST glycolytic metabolism with FDG-PET while pts were on or off TKI in prior trials of imatinib and sunitinib. We tested the same principle in a phase I trial of IPI-504, a novel potent inhibitor of Hsp90 (a chaperone for protein homeostasis) that results in selective destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. Methods: Twenty-one patients with metatastic and/or unresectable GIST following failure of prior therapy with TKI were treated with IPI-504. Serial FDG-PET imaging was performed at baseline, during the 1st cycle after at least 2 doses (C1, days 4–11, “ON”, n = 18), and at the end of the 10-day off-treatment period prior to the start of the 2nd cycle (C1, “OFF”, n = 20). A subset of 5 pts also had FDG-PET at the end of the 3rd cycle (C3, day 11, “ON”). Maximum standardized uptake values (SUVmax) were measured in up to 3 lesions/pt with the greatest FDG uptake, and the SUVmax of all lesions was summed at each time point. Percent change in the summed mean SUVmax was calculated at each time point relative to the previous scan. Temporal changes were evaluated in those pts showing more than a 10% decrease in SUVmax during C1 “ON” compared to baseline. Results: We observed a >10% reduction in SUVmax (mean = - 28%) during the 1st cycle (C1, “ON”) in 8/18 pts. All these pts showed an increase in SUVmax (mean = +29%) when off therapy (C1, “OFF”). Three of these 8 pts had a scan during cycle 3. All demonstrated a decrease in SUVmax (mean = -30%) while on the drug (C3, “ON”). Conclusion: These preliminary findings suggest that: (1) tumor metabolic response as measured with FDG-PET parallels the intermittent pattern of IPI-504 administration in this study as early as after the 2nd dose administration; and, (2) IPI-504 has a rapid downstream effect on glucose metabolism similar to that observed with TKIs despite the very different mechanism of action of IPI-504. The pattern of response to Hsp90 inhibition seen in this heavily pretreated population strongly supports further clinical investigation. No significant financial relationships to disclose.

Mineralocorticoid receptor degradation is promoted by Hsp90 inhibition and the ubiquitin-protein ligase CHIP

2010 ◽  
Vol 299 (6) ◽  
pp. F1462-F1472 ◽  
Author(s):  
Nourdine Faresse ◽  
Dorothée Ruffieux-Daidie ◽  
Mélanie Salamin ◽  
Celso E. Gomez-Sanchez ◽  
Olivier Staub
Keyword(s):  
Mineralocorticoid Receptor ◽  
Nuclear Translocation ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibition ◽  
Interacting Protein ◽  
Ubiquitin Protein Ligase ◽  
The Stability ◽  
Benzoquinone Ansamycin

The mineralocorticoid receptor (MR) plays a crucial role in the regulation of Na+ balance and blood pressure, as evidenced by gain of function mutations in the MR of hypertensive families. In the kidney, aldosterone binds to the MR, induces its nuclear translocation, and promotes a transcriptional program leading to increased transepithelial Na+ transport via the epithelial Na+ channel. In the unliganded state, MR is localized in the cytosol and part of a multiprotein complex, including heat shock protein 90 (Hsp90), which keeps it ligand-binding competent. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic that binds to Hsp90 and alters its function. We investigated whether 17-AAG affects the stability and transcriptional activity of MR and consequently Na+ reabsorption by renal cells. 17-AAG treatment lead to reduction of MR protein level in epithelial cells in vitro and in vivo, thereby interfering with aldosterone-dependent transcription. Moreover, 17-AAG inhibited aldosterone-induced Na+ transport, possibly by interfering with MR availability for the ligand. Finally, we identified the ubiquitin-protein ligase, COOH terminus of Hsp70-interacting protein, as a novel partner of the cytosolic MR, which is responsible for its polyubiquitylation and proteasomal degradation in presence of 17-AAG. In conclusion, 17-AAG may represent a novel pharmacological tool to interfere with Na+ reabsorption and hypertension.

scholarly journals Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Samantha Milanesi ◽  
Silvano Garibaldi ◽  
Michela Saio ◽  
Giorgio Ghigliotti ◽  
Daniela Picciotto ◽  
...  
Keyword(s):  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Indoxyl Sulfate ◽  
Collagen I ◽  
Hsp90 Inhibition ◽  
Fibroblast Activation ◽  
Tubular Necrosis ◽  
Pathway Activation ◽  
Potential Strategy ◽  
Dependent Pathway

Indoxyl sulfate (IS) accumulation occurs early during chronic kidney disease (CKD) progression and contributes to renal dysfunction by inducing fibrosis, inflammation, oxidative stress, and tissue remodeling. Renal toxicity of high IS concentrations (250 μM) has been widely explored, particularly in resident tubular and glomerular cells, while the effect of a moderate IS increase on kidneys is still mostly unknown. To define the effects of IS accumulation on renal fibroblasts, we first analyzed kidneys of C57BL/6 mice receiving IS (0.1%) in drinking water for 12 weeks. As a next step, we treated renal fibroblasts (NRK-49F) with IS (20 μM) with or without the HSP90 inhibitor 17-AAG (1 μM). In mouse kidneys, IS increased the collagen deposition and HSP90 and α-SMA expression (immunohistochemistry) in interstitial fibroblasts and caused tubular necrosis (histological H&E and picrosirius red staining). In NRK-49F cells, IS induced MCP1, TGF-β, collagen I, α-SMA, and HSP90 gene/protein expression and Smad2/3 pathway activation. IS had no effects on fibroblast proliferation and ROS production. 17-AAG counteracted IS-induced MCP1, TGF-β, collagen I, and α-SMA expression and Smad2/3 phosphorylation. Our study demonstrates that the IS increase promotes renal fibroblast activation by a HSP90-dependent pathway and indicates HSP90 inhibition as a potential strategy to restrain IS-induced kidney inflammation and fibrosis in CKD.

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