The glucocorticoid responses are shaped by molecular chaperones

Grad, Iwona; Picard, Didier

doi:10.1016/j.mce.2007.05.018

Cited by 372 publications

(288 citation statements)

References 103 publications

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“…Using a genomic DNA microarray containing the region of 800 bp upstream and 200 bp downstream of transcription start sites of 18,660 human genes, Laganière and his associates found that the promoter of SMYD3 could be bound by ERa in the presence of 17b-estradiol (6,7,16). Interestingly, our previous study had also shown that SMYD3 could decrease the effect of dexamethasone, a well-known glucocorticoid steroid hormone whose function is mediated through GR and required HSP90 (9,17). Combining these findings, it speculated that SMYD3 might be involved in the downstream pathway of ER, GR or some other nuclear hormone receptors.…”

Section: Discussionmentioning

confidence: 97%

Novobiocin decreases SMYD3 expression and inhibits the migration of MDA‐MB‐231 human breast cancer cells

Luo¹,

Zou²,

Wang³

et al. 2010

IUBMB Life

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SummarySET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis, and heat-shock protein HSP90A has been shown to increase the activity of SMYD3. We previously reported that overexpression of SMYD3 stimulated the migration of cells. In this study, we further found that novobiocin, a HSP90 inhibitor, could decrease the expression of SMYD3 and dose dependently inhibit the proliferation and migration of MDA-MB-231 human breast cancer cells. As a control, the short hairpin RNA (shRNA) targeting SMYD3 gene also showed similar effects with novobicin. This study is the first to show that novobiocin can inhibit the migration of breast cancer cells and such event may involve the downregulation of SMYD3. These findings might throw light on the development of novel therapeutic approaches to human cancers, and lend further understanding to the potential role of SMYD3 in human carcinogenesis.

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Section: Discussionmentioning

confidence: 97%

Novobiocin decreases SMYD3 expression and inhibits the migration of MDA‐MB‐231 human breast cancer cells

Luo¹,

Zou²,

Wang³

et al. 2010

IUBMB Life

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“…transferred from Hsp70 to Hsp90, where the final steps of folding are completed (2,3). While bound to the Hsp90, the client protein then becomes functional, e.g.…”

mentioning

confidence: 99%

Electrostatic Interactions of Hsp-organizing Protein Tetratricopeptide Domains with Hsp70 and Hsp90

Kajander

Sachs

Goldman

et al. 2009

Journal of Biological Chemistry

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The Hsp-organizing protein (HOP) binds to the C termini of the chaperones Hsp70 and Hsp90, thus bringing them together so that substrate proteins can be passed from Hsp70 to Hsp90. Because Hsp90 is essential for the correct folding and maturation of many oncogenic proteins, it has become a significant target for anti-cancer drug design. HOP binds to Hsp70 and Hsp90 via two independent tetratricopeptide (TPR) domains, TPR1 and TPR2A, respectively. We have analyzed ligand binding using Poisson-Boltzmann continuum electrostatic calculations, free energy perturbation, molecular dynamics simulations, and site-directed mutagenesis to delineate the contribution of different interactions to the affinity and specificity of the TPR-peptide interactions. We found that continuum electrostatic calculations could be used to guide protein design by removing unfavorable interactions to increase binding affinity, with an 80-fold increase in affinity for TPR2A. Contributions at buried charged residues, however, were better predicted by free energy perturbation calculations. We suggest using a combination of the two approaches for increasing the accuracy of results, with free energy perturbation calculations used only at selected buried residues of the ligand binding pocket. Finally we present the crystal structure of TPR2A in complex with its non-cognate Hsp70 ligand, which provides insight on the origins of specificity in TPR domain-peptide recognition.The Hsp-organizing protein (HOP) 4 plays a key role in in vivo folding by bringing the chaperones Hsp70 (or its constitutively expressed isoform, Hsp70) and Hsp90 together into a complex (1) (see Fig. 1), where specific substrate proteins are passed over from Hsp70 to Hsp90. Partially folded Hsp90 client proteins are transferred from Hsp70 to Hsp90, where the final steps of folding are completed (2, 3). While bound to the Hsp90, the client protein then becomes functional, e.g. hormone receptors can bind their ligands, and then are released. Both chaperones must be brought together by their interaction with HOP to accomplish this (see Fig. 1). The whole Hsp90 functional cycle involves also other co-chaperones, such as p23, other TPR proteins, and ATP binding and hydrolysis, and is fairly complicated and incompletely understood (4). However, it is clear that HOP facilitates the interaction of Hsp70 and Hsp90 and thus is important in providing the link between the chaperones in the early part of Hps90 functional cycle. Hsp90 client proteins include nuclear hormone receptors, p53, and other transcription factors and various kinases, such as Atk and Her2. Many of these are oncogenes, making Hsp90 a significant anti-cancer drug target (5). It is therefore of considerable importance to better understand the chaperone cycle of Hsp90 and in particular its interaction with essential co-chaperones, such as HOP. The interactions of Hsp70 and Hsp90 with HOP also provide an excellent model system in which to study the contribution of electrostatics to protein-peptide interactions, as will bec...

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“…Furthermore, HSP90 can repress the ability of AHR to bind to ARNT [35]. The role of HSP90 for AHR stability is comparable to the function of HSP90 for other ligand activated transcription factors such as the steroid receptors [36]. HSP90 associates with p23, a co-chaperone protein that binds to the ATP-bound form of HSP90 [33] and p23 takes part in the AHR complex [37].…”

Section: Hsp90 P23 and E3 Ubiquitin Ligasesmentioning

confidence: 99%

Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

Oliveira

Smolenski

2009

Biochemical Pharmacology

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Publication information Biochemical Pharmacology, 77 (4): 723-733Publisher Elsevier Item record/more information http://hdl.handle.net/10197/6007 Publisher's statementThis is the author's version of a work that was accepted for publication in Biochemical Pharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochemical Pharmacology (VOL 77, ISSUE 4, (2009)

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The glucocorticoid responses are shaped by molecular chaperones

Cited by 372 publications

References 103 publications

Novobiocin decreases SMYD3 expression and inhibits the migration of MDA‐MB‐231 human breast cancer cells

Novobiocin decreases SMYD3 expression and inhibits the migration of MDA‐MB‐231 human breast cancer cells

Electrostatic Interactions of Hsp-organizing Protein Tetratricopeptide Domains with Hsp70 and Hsp90

Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

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