Journal ArticleDOI
The Hsp90 molecular chaperone: an open and shut case for treatment
TLDR
The biology of the Hsp90 molecular chaperone is reviewed, emphasizing recent progress in the understanding of structure-function relationships and the identification of new client proteins.Abstract:
The molecular chaperone Hsp90 (90 kDa heat-shock protein) is a remarkably versatile protein involved in the stress response and in normal homoeostatic control mechanisms. It interacts with 'client proteins', including protein kinases, transcription factors and others, and either facilitates their stabilization and activation or directs them for proteasomal degradation. By this means, Hsp90 displays a multifaceted ability to influence signal transduction, chromatin remodelling and epigenetic regulation, development and morphological evolution. Hsp90 operates as a dimer in a conformational cycle driven by ATP binding and hydrolysis at the N-terminus. The cycle is also regulated by a group of co-chaperones and accessory proteins. Here we review the biology of the Hsp90 molecular chaperone, emphasizing recent progress in our understanding of structure-function relationships and the identification of new client proteins. In addition we describe the exciting progress that has been made in the development of Hsp90 inhibitors, which are now showing promise in the clinic for cancer treatment. We also identify the gaps in our current understanding and highlight important topics for future research.read more
Citations
More filters
Journal ArticleDOI
The genomic complexity of primary human prostate cancer
Michael F. Berger,Michael F. Berger,Michael S. Lawrence,Francesca Demichelis,Yotam Drier,Kristian Cibulskis,Andrey Sivachenko,Andrea Sboner,Raquel Esgueva,Dorothee Pflueger,Carrie Sougnez,Robert C. Onofrio,Scott L. Carter,Kyung Park,Lukas Habegger,Lauren Ambrogio,Timothy Fennell,Melissa Parkin,Gordon Saksena,Douglas Voet,Alex H. Ramos,Alex H. Ramos,Trevor J. Pugh,Trevor J. Pugh,Jane Wilkinson,Sheila Fisher,Wendy Winckler,Scott Mahan,Kristin G. Ardlie,Jennifer Baldwin,Jonathan W. Simons,Naoki Kitabayashi,Theresa Y. MacDonald,Philip W. Kantoff,Lynda Chin,Stacey Gabriel,Mark Gerstein,Todd R. Golub,Todd R. Golub,Todd R. Golub,Matthew Meyerson,Matthew Meyerson,Ashutosh Tewari,Eric S. Lander,Eric S. Lander,Eric S. Lander,Gad Getz,Mark A. Rubin,Levi A. Garraway,Levi A. Garraway +49 more
TL;DR: In this paper, the authors presented the complete sequence of seven primary human prostate cancers and their paired normal counterparts and revealed previously unknown balanced rearrangements, at which multiple intra-and inter-chromosomal loci exchange their breakpoint arms without any loss of genetic material.
Journal ArticleDOI
Biological and Chemical Approaches to Diseases of Proteostasis Deficiency
TL;DR: It is proposed that small molecules can enhance proteostasis by binding to and stabilizing specific proteins (pharmacologic chaperones) or by increasing the protestasis network capacity (proteostasis regulators) and that such therapeutic strategies, including combination therapies, represent a new approach for treating a range of diverse human maladies.
Journal ArticleDOI
Combinatorial drug therapy for cancer in the post-genomic era
TL;DR: The extraordinary intratumor genetic heterogeneity in cancers revealed by deep sequencing explains why de novo and acquired resistance arise with molecularly targeted drugs and cytotoxic chemotherapy, limiting their utility.
Journal ArticleDOI
Hsp90 molecular chaperone inhibitors: are we there yet?
Len Neckers,Paul Workman +1 more
TL;DR: Success will likely lie in treating cancers that are addicted to particular driver oncogene products that are sensitive Hsp90 clients, as well as malignancies in which buffering of proteotoxic stress is critical for survival.
Journal ArticleDOI
System-wide changes to SUMO modifications in response to heat shock
Filip Golebiowski,Ivan Matic,Michael H. Tatham,Christian Cole,Yili Yin,Akihiro Nakamura,Juergen Cox,Geoffrey J. Barton,Matthias Mann,Ronald T. Hay +9 more
TL;DR: This comprehensive proteomic analysis of the substrates of a ubiquitin-like modifier (Ubl) identifies a pervasive role for SUMO proteins in the biologic response to hyperthermic stress.
References
More filters
Journal ArticleDOI
Hepatitis B virus infection [1] (multiple letters)
Journal ArticleDOI
Hepatitis B virus infection.
TL;DR: This review addresses many aspects of HBV infection, including the role of the immune system in determining the outcome of clinical infection, recent developments in molecular studies of the virus, and new treatments capable of eradicating chronic infection.
Journal ArticleDOI
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.
Journal ArticleDOI
Nod1 Detects a Unique Muropeptide from Gram-Negative Bacterial Peptidoglycan
Stephen E. Girardin,Ivo G. Boneca,Leticia A.M. Carneiro,Aude Antignac,Muguette Jéhanno,Jérôme Viala,Karsten Tedin,Muhamed-Kheir Taha,Agnès Labigne,Ulrich Zähringer,Anthony J. Coyle,Peter S. DiStefano,John Bertin,Philippe J. Sansonetti,Dana J. Philpott +14 more
TL;DR: It is shown that human Nod1 specifically detects a unique diaminopimelate-containing N-acetylglucosamine–N-acetelmuramic acid tripeptide motif found in Gram-negative bacterial peptidoglycan, resulting in activation of the transcription factor NF-κB pathway.
Journal ArticleDOI
Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation.
TL;DR: It is demonstrated that HSP participation in multimolecular complex formation is required for src-mediated transformation and can provide a target for drug modulation.