Heat shock proteins as emerging therapeutic targets

Sőti, Csaba; Nagy, Enikő; Giricz, Zoltán; Vı́gh, László; Csermely, Péter; Ferdinándy, Péter

doi:10.1038/sj.bjp.0706396

Cited by 345 publications

(267 citation statements)

References 160 publications

(180 reference statements)

Supporting

Mentioning

253

Contrasting

Unclassified

Order By: Relevance

“…Similarly, myo-inositol and betaine, organic osmolytes, play protective roles against various stimulations as well as hyperosmotic stress through their transporter systems, SMIT and BGT-1, respectively, in several types of cells and organs (53,54), although further studies will be required to elucidate their biological functions in cardiac myocytes. Moreover, Hsp70-2 preserves myocardial function and prevents apoptosis (55,56). Importantly, Hsp70-2 has been demonstrated to be involved in the cytoprotective process against Dox exposure (57).…”

Section: Discussionmentioning

confidence: 99%

Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes

Ito

Fujio

Takahashi

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Nuclear factor-activated T cell 5 (NFAT5), a novel member of the NFAT family of proteins, was originally identified as a transcriptional factor responsible for adaptation to hyperosmotic stress. Though NFAT5 is ubiquitously expressed, the biological functions of NFAT5 remain to be clarified, especially in the tissues that are not exposed to hypertonicity, including hearts. In the present study, we focused on the cardioprotective roles of NFAT5 against the cardiotoxic anti-tumor agent doxorubicin (Dox). In cultured cardiomyocytes, transcripts of the hypertonicity-inducible genes, such as taurine transporter (TauT) and sodium/myo-inositol transporter, were down-regulated by Dox. Interestingly, NFAT5 protein, but not mRNA, was decreased in cardiomyocytes exposed to Dox. Treatment of proteasome inhibitors, MG-132 or proteasome-specific inhibitor 1, prevented the Dox-mediated decrease of NFAT5 protein. Further, ubiquitin-conjugated NFAT5 was not detected in cultured cardiomyocytes treated with MG-132 and/or Dox, as assessed by immunoprecipitation assay, suggesting Dox-induced degradation through ubiquitin-independent proteasome pathway. Importantly, inhibition of NFAT5 with overexpression of dominant-negative NFAT5 decreased cell viability and increased creatine kinase leakage into culture medium. Consistently, small interfering RNA targeting NFAT5 gene enhanced myocyte death. These findings suggest that Dox promoted the degradation of NFAT5 protein, reducing cell viability in cardiomyocytes. This is the first demonstration that NFAT5 is a positive regulator of cardiomyocyte survival.Because mature cardiac myocytes have a limited proliferative potential, accumulation of cardiomyocyte death leads to heart failure. Pathologically, cardiac myocyte death is induced by various kinds of stresses, such as hypoxia, mechanical stress, and cardiotoxic drugs. Among them, doxorubicin (Dox), 2 an antitumor agent of the anthracycline family, is well known to have a harmful effect and its use is limited by irreversible cardiotoxicity (1, 2). Although the precise mechanisms of its myocardial damage are unclear, numerous evidence suggests that Dox induces cardiotoxicity through multiple pathways, including production of reactive oxygen species, perturbation of calcium handling, and selective inhibition of cardiac muscle-specific gene expression (1,3,4). Recently, several reports indicate that Dox activates proteasome-mediated proteolysis that results in the disorder of cardiac gene expression (5, 6).NFAT5 (nuclear factor-activated T cell 5)/TonEBP (tonicityresponse element-binding protein), a member of the rel/NF B/ NFAT family of transcription factors, was originally identified as a transcriptional factor involved in the cellular responses to hypertonic stress (7, 8). Whereas NFAT 1-4 are activated by Ca 2ϩ /calcineurin pathway, NFAT5 activity is regulated in a calcineurin-independent manner, because it lacks the N-terminal NFAT homology region containing the calcineurin regulatory motif (7,8). NFAT5 is activated by phosphorylation ...

show abstract

Section: Discussionmentioning

confidence: 99%

Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes

Ito

Fujio

Takahashi

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…It binds to an ATP binding site unique to HSP90. 14 This binding prevents conformational changes in HSP90 that are required for chaperone function. 15 Unfortunately, GA has low systemic duration (3-4 h) and causes acute hepatic necrosis when administered in vivo.…”

Section: Introductionmentioning

confidence: 99%

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

View full text Add to dashboard Cite

Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

show abstract

“…Hormone-binding assays were performed as in ref. 36, except that our reactions (40 l) contained 10 l of in vitro-expressed GR (1-10 pmol), 0-300 M coactivator or Hsp90 peptides, and 2-50 nM [1,2,4,6, H]dex (Amersham Pharmacia, Piscataway, NJ).…”

Section: Gr-hsp90mentioning

confidence: 99%

“…Hsp90 is essential for the viability of eukaryotic cells and has become a prime therapeutic target for a variety of human diseases (2).…”

mentioning

confidence: 99%

Unliganded and hormone-bound glucocorticoid receptors interact with distinct hydrophobic sites in the Hsp90 C-terminal domain

Fang

Ricketson

Getubig

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Unlike most chaperones, heat-shock protein 90 (Hsp90) interacts with a select group of ''client proteins'' that regulate essential biological processes. Little is known about how Hsp90 recognizes and binds these proteins. The glucocorticoid receptor (GR) is a well characterized Hsp90 client protein, whose hormone binding, nuclear-cytoplasmic trafficking, and transcriptional activity are regulated by Hsp90. Here, we provide evidence that unliganded and hormone-bound GR interact with two distinct, solventexposed hydrophobic sites in the Hsp90 C-terminal domain that contain the sequences ''MxxIM'' (HM10) and ''L/MxxIL'' (HM9). Our results indicate that binding of Hsp90 HM10 to unliganded GR stabilizes the unliganded ligand-binding pocket of GR indirectly by promoting an intramolecular interaction between the C-terminal ␣-helix (H12) and a solvent-exposed hydrophobic groove in the GR ligand binding domain. In the presence of hormone, Hsp90 appears to bind the hydrophobic groove of GR directly by mimicking the interactions of GR with transcriptional coactivators. The identified interactions provide insights into the mechanisms that enable Hsp90 to regulate the activity of both unliganded and hormonebound GR and to sharpen the cellular response to hormone.binding sites ͉ heat-shock protein 90 ͉ steroid hormone receptors

show abstract

Heat shock proteins as emerging therapeutic targets

Cited by 345 publications

References 160 publications

Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes

Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Unliganded and hormone-bound glucocorticoid receptors interact with distinct hydrophobic sites in the Hsp90 C-terminal domain

Contact Info

Product

Resources

About