Heat shock protein 90

Neckers, Len; Ivy, S. Percy

doi:10.1097/00001622-200311000-00003

Cited by 379 publications

(282 citation statements)

References 36 publications

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“…Thus mutations that allow a kinase to develop "fast" activity also result in the kinase becoming structurally "loose," with Cdc37 and Hsp90 helping maintain this "fast and loose" existence. Hsp90 inhibitors are currently undergoing clinical trial 4 . Understanding the dynamics of kinaseCdc37-Hsp90 interaction may be of particular significance for prediction of kinases in cancer cells most adversely affected by Hsp90 and/or Cdc37 inhibition and facilitation of anti-Cdc37 drug design.…”

Section: Structural Mechanisms Of Cdc37-kinase Interactionmentioning

confidence: 99%

“…Hsp90 is a facilitator of oncogenesis that stabilizes a wide range of overexpressed or mutated oncogenic proteins and permits their tumorigenic influence to arise 3,7 . Tumors thus appear to become addicted to chaperones and can be treated by withdrawing the chaperoning power of Hsp90 [4][5][6] . Cdc37 interacts with a subset of client proteins within Hsp90 complexes and plays a specialized role as primary partner in kinome maintenance 3,8,9 .…”

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Targeting the oncogene and kinome chaperone CDC37

et al. 2008

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Cdc37 is a molecular chaperone that physically stabilizes the catalytic domains found in protein kinases and is therefore a wide-spectrum regulator of protein phosphorylation. It is also an overexpressed oncogene that mediates carcinogenesis by stabilizing the compromised structures of mutant and/or overexpressed oncogenic kinases. Recent work shows that such dependency of malignant cells on elevated Cdc37 expression is a vulnerability that can be targeted in cancer by agents that deplete or inhibit Cdc37. Cdc37 is thus a candidate for broad-spectrum molecular cancer therapy.Although Cdc37 is overexpressed in a number of cancers, it is an unusual oncoprotein whose transforming character does not readily snap into place in the conventional oncogenic pathways. Instead, it is a molecular chaperone, a protein that facilitates folding/refolding of other proteins, often described as its "clients". The role of molecular chaperones in cancer was first characterized with regard to Hsp90 (for review see 5 ). Hsp90 is a facilitator of oncogenesis that stabilizes a wide range of overexpressed or mutated oncogenic proteins and permits their tumorigenic influence to arise 3,7 . Tumors thus appear to become addicted to chaperones and can be treated by withdrawing the chaperoning power of Hsp90 [4][5][6] . Cdc37 interacts with a subset of client proteins within Hsp90 complexes and plays a specialized role as primary partner in kinome maintenance 3,8,9 . This specialized property of Cdc37 fuels the acceleration of cell proliferation observed in cancer by promoting the activities of a broad array of protein kinases 1-3 . These include receptor tyrosine kinases such as EGFR and MET, non-receptor tyrosine kinases v-src and Lck, and intracellular serine/threonine kinases Raf-1, Ksr, Akt, IKK, Cdc2, Cdk2 and Cdk4. A comprehensive list of Cdc37 client kinases, including the ones listed above and others can be found at the website of Dr Didier Picard: http://www.picard.ch/downloads/Cdc37interactors.pdf. The degree of dependency of the cancer cell kinome on Cdc37 expression thus appears to be extensive and in a recent yeast screen, at least 90 % of the protein kinases examined required Cdc37 for function 10 .The defining cellular role for Cdc37, which becomes misappropriated in cancer, resides in its promotion of cell proliferation. Indeed this protein was first discovered in a yeast screen for cell division cycle proteins, hence its name 11 . Thus when mammalian tissues undergo rapid proliferation during development, the normally scarce levels of Cdc37 are rapidly expanded. Elevated levels of Hsp90/Cdc37 complexes mediate the maturation and stabilization of protein 3Correspondence to: Stuart K. Calderwood, 21-27 Burlington Ave. Rm. 553B, Boston, MA 02215, scalderw@bidmc.harvard.edu. 2 Current address: Johns Hopkins University School of Medicine, Baltimore, MD 21205Because of space limitations we were unable to cite many significant studies on Cdc37 and Hsp90. We apologize to the authors of such studies and refer to excellent pu...

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Section: Structural Mechanisms Of Cdc37-kinase Interactionmentioning

confidence: 99%

mentioning

confidence: 99%

Targeting the oncogene and kinome chaperone CDC37

et al. 2008

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“…Many of Hsp90's client proteins, including p53, Cdk4, csrc and v-src, are oncogenic or otherwise required for cell proliferation, making Hsp90 an attractive target for anti-cancer therapeutics (Neckers, 2007). Inhibition of Hsp90 with small molecules such as geldanamycin and its derivatives has been shown to be antitumorigenic, and several of these compounds are currently in clinical trials (Chiosis et al, 2003;Neckers & Ivy, 2003;Solit et al, 2008;Workman, 2004). Hsp90 has also been implicated in other diseases including Alzheimers (Dickey et al, 2008), vascular disease (Shah et al, 1999), and viral diseses (Geller et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

271

262

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The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

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“…AR is nearly ubiquitous in mammalian tissues sequestered and stabilized in the cytoplasm bound to heat shock proteins. 6 Upon binding testosterone or dihydrotestosterone, it undergoes a series of conformational changes that lead to translocation to the nucleus, allowing interactions with androgen response elements at various androgen target genes. 7,8 Besides transcription factor functions, AR is important in integrating cellular signals by interacting with central signal-transduction pathways.…”

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confidence: 99%

Androgen receptor and prostate cancer

Richter

Srivastava

Dobi

2007

Prostate Cancer Prostatic Dis

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Since the original observations of Huggins and Hodges that prostate cancers are androgen dependent, androgen ablation therapy has been the gold standard for the treatment of advanced prostate cancer (CaP). Androgen receptor (AR) is believed to play critical roles in the development and progression of CaP. Treatment for neoadjuvant, adjuvant and recurrent disease all center on the regulation and manipulation of the androgen pathway, in which AR plays an integral role. Recent discoveries that frequent overexpression of ETS-related proto-oncogenes may be driven by AR as a consequence of common genomic rearrangements can hold the key towards the understanding of early phases of prostate cancer. Furthermore, AR function evolves as the cell changes towards a clinically androgen depletion independent state. Comprehension of AR function, regulation and abnormalities are increasingly refined towards the understanding of the role of AR in CaP, and in therapeutic applications. Development of future therapy for CaP will be aided by improving the knowledge of dysfunctions of AR and its network in prostate cancer. This review focuses salient features of AR and on the recent advances addressing AR dysfunctions in prostate cancer.

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Heat shock protein 90

Cited by 379 publications

References 36 publications

Targeting the oncogene and kinome chaperone CDC37

Targeting the oncogene and kinome chaperone CDC37

Conformational dynamics of the molecular chaperone Hsp90

Androgen receptor and prostate cancer

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