Journal ArticleDOI
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
TLDR
Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.Abstract:
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins (known as clients). Clients are enriched in signal transducers, including kinases and transcription factors. Therefore, HSP90 regulates diverse cellular functions and exerts marked effects on normal biology, disease and evolutionary processes. Recent structural and functional analyses have provided new insights on the transcriptional and biochemical regulation of HSP90 and the structural dynamics it uses to act on a diverse client repertoire. Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.read more
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17-demethoxy-reblastatin, an Hsp90 inhibitor, induces mitochondria-mediated apoptosis through downregulation of Mcl-1 in human hepatocellular carcinoma cells
TL;DR: The results indicated that 17-DR possessed potent anticancer effects on HCC cells by inhibiting cell proliferation and inducing apoptosis, and its underlying mechanisms.
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Feasibility and safety of targeting mitochondria for cancer therapy – preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor
TL;DR: Gamitrinib treatment is unremarkable in dogs with no alterations in clinical-chemistry parameters, heart function, or tissue histology, and causes occasional inflammation at the infusion site and mild elevation of serum urea nitrogen in rats, indicating that targeting mitochondria for cancer therapy is feasible and well tolerated.
Journal ArticleDOI
Evolution of kinase polypharmacology across HSP90 drug discovery.
TL;DR: In this paper, the authors use computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors and demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology.
Journal ArticleDOI
Comparative Transcriptome Analysis of Gene Expression Patterns in Tomato Under Dynamic Light Conditions
TL;DR: The results expand the understanding of plant development and photosynthetic regulations under DL conditions by multiple pathways, predominantly of plant–pathogen interactions, plant hormone signal transductions, metabolites, and photosynthesis.
Journal ArticleDOI
Heat Shock Protein 90 Ensures the Integrity of Rubella Virus p150 Protein and Supports Viral Replication.
Masafumi Sakata,Hiroshi Katoh,Noriyuki Otsuki,Kiyoko Okamoto,Yuichiro Nakatsu,Chang-Kweng Lim,Masayuki Saijo,Makoto Takeda,Yoshio Mori +8 more
TL;DR: The treatment of RUBV-infected cells with the HSP90 inhibitors 17-allylamino-17-desmethoxygeldanamycin (17-AAG) and ganetespib suppressed RubV genome replication demonstrated that RUBv p150 is a client of the H SP90 molecular chaperone and that HSP 90 functions as a key host factor for RUBVs replication.
References
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Mechanism of Activation of the Raf-Erk Signaling Pathway by Oncogenic Mutations of B-Raf
Paul T C Wan,Mathew J. Garnett,S. Mark Roe,Sharlene Lee,Dan Niculescu-Duvaz,Valerie M. Good,Cancer Genome,C. Michael Jones,Christopher J. Marshall,Caroline J. Springer,David Barford,Richard Marais +11 more
TL;DR: The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
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HSP90 and the chaperoning of cancer.
TL;DR: Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise.
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Hsp90 as a capacitor for morphological evolution
TL;DR: It is reported that when Drosophila Hsp90 is mutant or pharmacologically impaired, phenotypic variation affecting nearly any adult structure is produced, with specific variants depending on the genetic background and occurring both in laboratory strains and in wild populations.
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Adapting proteostasis for disease intervention.
TL;DR: The proteostasis network is described, a set of interacting activities that maintain the health of proteome and the organism that has the potential to ameliorate some of the most challenging diseases of this era.
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Function and regulation of cullin-RING ubiquitin ligases.
TL;DR: This review focuses on the composition, regulation and function of cullin–RING ligases, and describes how these enzymes can be characterized by a set of general principles.