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
Citations
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Journal ArticleDOI
Genome Sequence of Saccharomyces carlsbergensis, the World's First Pure Culture Lager Yeast
TL;DR: In this article, the authors sequenced S. carlsbergensis using next generation sequencing technologies and showed that the 19.5-Mb genome is substantially larger than the S. cerevisiae genome.
Journal ArticleDOI
Heat shock protein 90 from Escherichia coli collaborates with the DnaK chaperone system in client protein remodeling
TL;DR: In vitro protein reactivation assays indicate that E. coli Hsp90 and DnaK interact in vivo and in vitro, providing additional evidence to suggest that E- coli HSp90 and the DNAK system function together.
Journal ArticleDOI
Uncovering a region of heat shock protein 90 important for client binding in E. coli and chaperone function in yeast.
Olivier Genest,Michael Reidy,Timothy O. Street,Joel R. Hoskins,Jodi L. Camberg,David A. Agard,Daniel C. Masison,Sue Wickner +7 more
TL;DR: In this paper, the authors developed a screen to identify Hsp90-defective mutants in E. coli and constructed homologous mutations in S. cerevisiae Hsp82 and identified several that caused defects in chaperone activity.
Journal ArticleDOI
Hypoxia inducible factor pathway inhibitors as anticancer therapeutics
TL;DR: The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation, and indirectly affects HIF but there have been no clinically approved direct HIF inhibitors.
Journal ArticleDOI
A Phase I Study of PF-04929113 (SNX-5422), an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Patients with Refractory Solid Tumor Malignancies and Lymphomas
Arun Rajan,Ronan J. Kelly,Jane B. Trepel,Yeong Sang Kim,Sylvia V. Alarcon,Shivaani Kummar,Martin Gutierrez,Sonja Crandon,Wadih M. Zein,Lokesh Jain,Baskar Mannargudi,William D. Figg,Brett E. Houk,Michael Shnaidman,Nicoletta Brega,Giuseppe Giaccone +15 more
TL;DR: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90 and has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study.
References
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Journal ArticleDOI
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.
Journal ArticleDOI
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.