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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Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33
Ninel Azoitei,Christopher M. Hoffmann,Jana M. Ellegast,Claudia R. Ball,Kerstin Obermayer,Ulrike Gößele,Britta Koch,Katrin Faber,Felicitas Genze,Mark Schrader,Hans A. Kestler,Hartmut Döhner,Gabriela Chiosis,Hanno Glimm,Stefan Fröhling,Claudia Scholl +15 more
TL;DR: HSP90 inhibition depletes STK33 in KRAS mutant tumors in KRas mutant tumors and results in down-regulation of HSP90 activity in these patients with KRAS mutated tumors.
Journal ArticleDOI
Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice
Iolanda Lázaro,Ainhoa Oguiza,Carlota Recio,Beñat Mallavia,Julio Madrigal-Matute,Julio Madrigal-Matute,Julia Blanco,Jesús Egido,José Luis Martín-Ventura,Carmen Gomez-Guerrero +9 more
TL;DR: HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.
Journal ArticleDOI
DangER: protein ovERload. Targeting protein degradation to treat myeloma
TL;DR: The various pathways used by myeloma cells for survival are discussed, with particular emphasis on the emerging role and conundrum of autophagy, as well as highlighting pre-clinical research on novel inhibitors targeting protein handling pathways.
Journal ArticleDOI
Systematic Proteomic Identification of the Heat Shock Proteins (Hsp) that Interact with Estrogen Receptor Alpha (ERα) and Biochemical Characterization of the ERα-Hsp70 Interaction
TL;DR: It is found that 21 Hsps and 3 Hsp cochaperones were associated with ERα in human 293T cells that were cultured in a medium containing necessary elements for cell proliferation and Interestingly, the ERα-Hsp70-1/Hsc70 interactions were detected only in the cytoplasm but not in the nucleus under hormone starvation conditions, and stimulation of the starved cells with 17β-estradiol (E2) did not change this.
Journal ArticleDOI
Hsp90 inhibitors as senolytic drugs to extend healthy aging.
TL;DR: The significance of developing senotherapeutic approaches to specifically kill senescent cells (senolytics) or suppress the senescence-associated secretory phenotype (SASP) that drives sterile inflammation associated with aging to extend healthspan and potentially lifespan is highlighted.
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.