scholarly journals Chromatin Recycling of Glucocorticoid Receptors: Implications for Multiple Roles of Heat Shock Protein 90

1999 ◽  
Vol 13 (3) ◽  
pp. 355-365 ◽  
Author(s):  
Jimin Liu ◽  
Donald B. DeFranco
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Nuclear Export ◽  
Glucocorticoid Receptors ◽  
Binding Capacity ◽  
Heat Shock Protein 90 ◽  
Multiple Roles ◽  
Chromatin Binding ◽  
Hormone Binding ◽  
Permeabilized Cells

Abstract Unliganded glucocorticoid receptors (GRs) released from chromatin after hormone withdrawal remain associated with the nucleus within a novel subnuclear compartment that serves as a nuclear export staging area. We set out to examine whether unliganded nuclear receptors cycle between distinct subnuclear compartments or require cytoplasmic transit to regain hormone and chromatin-binding capacity. Hormone-withdrawn rat GrH2 hepatoma cells were permeabilized with digitonin to deplete cytoplasmic factors, and then hormone-binding and chromatin-binding properties of the recycled nuclear GRs were measured. We found that recycled nuclear GRs do not require cytosolic factors or ATP to rebind hormone. Nuclear GRs that rebind hormone in permeabilized cells target to high-affinity chromatin-binding sites at 30 C, but not 0 C, in the presence of ATP. Since geldanamycin, a heat shock protein-90 (hsp90)-binding drug, inhibits hormone binding to recycled nuclear GRs, hsp90 may be required to reassemble the receptor into a form capable of productive interactions with hormone. Geldanamycin also inhibits GR release from chromatin during hormone withdrawal, suggesting that hsp90 chaperone function may play multiple roles to facilitate chromatin recycling of GR.

scholarly journals Subnuclear Trafficking of Glucocorticoid Receptors In Vitro: Chromatin Recycling and Nuclear Export

1997 ◽  
Vol 137 (3) ◽  
pp. 523-538 ◽  
Author(s):  
Jun Yang ◽  
Jimin Liu ◽  
Donald B. DeFranco
Keyword(s):  
Heat Shock ◽  
Nuclear Export ◽  
Glucocorticoid Receptors ◽  
Kinase Inhibitors ◽  
Tyrosine Phosphatase ◽  
Sodium Molybdate ◽  
Hnrnp A1 ◽  
Permeabilized Cells ◽  
Subnuclear Trafficking

We have used digitonin-permeabilized cells to examine in vitro nuclear export of glucocorticoid receptors (GRs). In situ biochemical extractions in this system revealed a distinct subnuclear compartment, which collects GRs that have been released from chromatin and serves as a nuclear export staging area. Unliganded nuclear GRs within this compartment are not restricted in their subnuclear trafficking as they have the capacity to recycle to chromatin upon rebinding hormone. Thus, GRs that release from chromatin do not require transit through the cytoplasm to regain functionality. In addition, chromatin-released receptors export from nuclei of permeabilized cells in an ATP- and cytosol-independent process that is stimulated by sodium molybdate, other group VI-A transition metal oxyanions, and some tyrosine phosphatase inhibitors. The stimulation of in vitro nuclear export by these compounds is not unique to GR, but is restricted to other proteins such as the 70- and 90-kD heat shock proteins, hsp70 and hsp90, respectively, and heterogeneous nuclear RNP (hnRNP) A1. Under analogous conditions, the 56-kD heat shock protein, hsp56, and hnRNP C do not export from nuclei of permeabilized cells. If tyrosine kinase inhibitors genistein and tyrphostin AG126 are included to prevent increased tyrosine phosphorylation, in vitro nuclear export of GR is inhibited. Thus, our results are consistent with the involvement of a phosphotyrosine system in the general regulation of nuclear protein export, even for proteins such as GR and hnRNP A1 that use distinct nuclear export pathways.

Evidence that the hormone binding domain of steroid receptors confers hormonal control on chimeric proteins by determining their hormone-regulated binding to heat-shock protein 90

Biochemistry ◽  
1993 ◽  
Vol 32 (20) ◽  
pp. 5381-5386 ◽  
Author(s):  
Lawrence C. Scherrer ◽  
Didier Picard ◽  
Enrique Massa ◽  
Jeffrey M. Harmon ◽  
S. Stoney Simons ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Steroid Receptors ◽  
Heat Shock Protein 90 ◽  
Hormonal Control ◽  
Binding Domain ◽  
Chimeric Proteins ◽  
Hormone Binding ◽  
Hormone Binding Domain

scholarly journals Kajian Heat Shock Protein 90 (HSP90) dalam Pencarian Kandidat Penghambatnya melalui Ekplorasi Bahan Alam Indonesia

2019 ◽  
Vol 5 (1) ◽  
pp. 1-11
Author(s):  
Rehmadanta Sitepu
Keyword(s):  
Clinical Trials ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Tyrosine Kinases ◽  
Glucocorticoid Receptors ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Hsp90 Inhibitors ◽  
Protein Activity ◽  
Third Phase

Exploration on anticancer candidates on inhibition of Heat Shock Protein (HSP) activity are increasing in the past ten years. Some of HSP90 inhibitor candidates were in third phase of clinical trials. However, this issue is not followed by the emergency of HSP90 inhibitor research in Indonesia, not only study on natural source but also on synthetic candidates. This study aims to look the development of tracking HSP90 inhibitor candidates globally so that it can initiate the related research in Indonesia. Study of HSP90 and its inhibitors were taken from scientific articles in the range from 2009 to 2018. HSP90 and its inhibitors have important values in the dynamics of functions and stability of proteins to maintain survival of cells. This also include the oncogene proteins that involve in cell proliferation such as tyrosine kinases, transcription factors, and regulatory proteins that expression and interaction depend on HSP90. Expression of the transcription factor p53, Alk gene, Wnt gene, glucocorticoid receptors have also links with HSP90 protein activity. Some candidates for inhibitor of HSP90 have been entering clinical trials such as geldanamycin analogues, resorcinol derivatives, and purines analog. Candidates from natural sources that are also being developed such as luteolin, licochalcone A, oleochantal, novobiocin, epigallocathecin gallat, silybin, deguelin, and celastrol from terpenoid class, Apigenin from flavon class, Curcumin, and  Gambogat Acid. HSP90 inhibitors which are entering the third phase of clinical trial are ganetespib from the resorcinol derivative and retaspimycin from geldanamisin analog group. Exploration of HSP90 inhibitors from Indonesia natural resources still have great potential to be developed because they have high impact values as anticancer candidates.

Synergistic Inhibition of the Glucocorticoid Receptor by Radicicol and Benzoquinone Ansamycins

2001 ◽  
Vol 382 (3) ◽  
pp. 499-504 ◽  
Author(s):  
Marcus C. Rosenhagen ◽  
Jason C. Young ◽  
Gabriela M. Wochnik ◽  
Alexandra S. Herr ◽  
Ulrike Schmidt ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Glucocorticoid Receptor ◽  
Nuclear Receptors ◽  
Therapeutic Target ◽  
Heat Shock Protein 90 ◽  
Model System ◽  
Hormone Binding ◽  
Synergistic Inhibition ◽  
Benzoquinone Ansamycin

Abstract Radicicol (RAD) and the benzoquinone ansamycin geldanamycin (GA) are potential anticancer drugs known to inhibit heat shock protein 90 (hsp90) and, therefore, the activation of proteins dependent on its function such as protooncogenic kinases and nuclear receptors. Using the glucocorticoid receptor (GR) as a model system we analysed the effects of RAD and various benzoquinone ansamycins. All compounds efficiently abolished GRdependent transactivation. Surprisingly, whenever one of the ansamycins was applied in combination with RAD, synergistic inhibition of GRdependent transcription and of hormone binding of GR was observed. In contrast, combination of two ansamycins showed no synergy. These findings suggest synergism within the hsp90 dimer and may open new ways to explore hsp90 as therapeutic target.

scholarly journals Distinct functions of the 90 kDa heat-shock protein (hsp90) in oestrogen and mineralocorticosteroid receptor activity: effects of hsp90 deletion mutants

1995 ◽  
Vol 311 (3) ◽  
pp. 797-804 ◽  
Author(s):  
N Binart ◽  
M Lombès ◽  
E E Baulieu
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Steroid Receptors ◽  
Binding Capacity ◽  
Hormone Binding ◽  
Affinity Ligand

Recent studies have confirmed that the 90 kDa heat-shock protein (hsp90) interacts both in vitro and in vivo with steroid receptors, encouraging further detailed physicochemical and functional analysis of its chaperone role. Thus, to explore the relationship between hsp90 and receptors, the baculovirus system was used to overexpress the chick hsp90 alpha (chsp90) along with the chick oestradiol receptor (cER) or the human mineralocorticosteroid receptor (hMR). These receptors were able to form 9 S complexes with chsp90, demonstrating the association of the co-expressed recombinant proteins. Three mutants of chsp90 (delta A, delta B and delta Z) have been created by deletion of the A (residues 221-290) and B (530-581) regions, rich in charged amino acids, and the Z (392-419) region, a putative leucine zipper. After co-expression, anti-receptor antibodies immunoprecipitated the cER or hMR complexed with the wild-type chsp90, the delta B or the delta Z mutant, but not with the delta A chsp90, indicating that deletion of the A region of chsp90 leads to a lack of interaction with these receptors. The hormone binding capacity of the cER was unaffected after its co-expression with each of the three mutants. In contrast, the hMR co-expressed with the delta B mutant failed to bind aldosterone, a finding confirmed in vivo by the absence of hormone-induced hMR nuclear translocation. Thus the B region is required for high-affinity ligand binding by the hMR. Our results suggest that the A region (but not the B or Z regions) is involved in binding of chsp90 to the cER and hMR, while the B region is essential for hormone binding by the hMR, consistent with a chaperone function for hsp90.

Glycyrrhizin effects rat hepatocytes via the reduction of heat shock protein 90 expression

2001 ◽  
Vol 120 (5) ◽  
pp. A357-A357
Author(s):  
T YOH ◽  
T NAKASHIMA ◽  
Y SUMIDA ◽  
Y KAKISAKA ◽  
H ISHIKAWA ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Rat Hepatocytes

430: Modulation of Heat-Shock Protein 90 (HSP90) Client Protein Expression in Prostate Cancer Cells by a Novel Novobiocin Analog

2006 ◽  
Vol 175 (4S) ◽  
pp. 140-140
Author(s):  
Manlio A. Goetzl ◽  
Brian S. Blagg ◽  
Benjamin Cronk ◽  
Len Neckers ◽  
Jeffrey M. Holzbeierlein
Keyword(s):  
Prostate Cancer ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Protein Expression ◽  
Cancer Cells ◽  
Heat Shock Protein 90 ◽  
Client Protein ◽  
Prostate Cancer Cells ◽  
Hsp90 Client Protein
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