| Regulation of calcineurin activity in insulin-secreting cells: stimulation by Hsp90 during glucocorticoid-induced apoptosis. | |
| | |
MedLine Citation:
|
PMID: 18611438 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Previously, we described that apoptotic cell death induced by the synthetic glucocorticoid dexamethasone (dex) is inhibited by calcineurin inhibitors, FK506 and deltamethrin, in insulin-secreting cells. The aim of the present study was to examine the mechanism of dex-dependent activation of calcineurin. In INS-1 cells cultured up to 4d with dex (100 nmol/l), the percentage of apoptosis, quantified by condensed nuclei and TUNEL positive cells, increased from 1% to 10.9%. FK506 inhibited dex-mediated cell death. Apoptosis was significantly higher at glucose concentrations that induce [Ca(2+)](i) oscillations than at low, non-stimulatory glucose. Dex had no acute effect on [Ca(2+)](i). Calcineurin activity, measured in control and dex-treated cell homogenates, revealed that maximal activity and the sensitivity to the substrate RII peptide was unaltered. However, dex treatment significantly increased enzyme activity at submaximal, physiological Ca(2+) concentrations. Dex did not stimulate the Ca(2+)-dependent protease calpain, known to activate calcineurin by cleavage, as no cleaved calcineurin was detectable. Furthermore, the calpain inhibitor ALLN did not counteract dex-dependent cell death. Western blotting revealed that in dex-treated cells heat shock protein 90 (Hsp90), a component of the glucocorticoid receptor (GR) known to stimulate calcineurin, was increased while calcineurin protein levels were unchanged. In immunoprecipitates with calcineurin antibodies, Hsp90 was only detected in dex-treated cell homogenates. These data suggest that dex-induced apoptosis involves release of Hsp90 from the stimulated GR complex, subsequent binding to and activation of calcineurin, that may contribute to dex-mediated cell death in the presence of high glucose. |
| | |
Authors:
|
Felicia Ranta; Martina Düfer; Björn Stork; Sebastian Wesselborg; Gisela Drews; Hans-Ulrich Häring; Florian Lang; Susanne Ullrich |
Related Documents
:
|
11108958 - The alg-2/aip-complex, a modulator at the interface between cell proliferation and cell... 2828158 - Somatic effects of p element activity in drosophila melanogaster: pupal lethality. 16374548 - Role of the unfolded protein response in cell death. 20550618 - Microrna-155 prevents necrotic cell death in human cardiomyocyte progenitor cells via t... 3338718 - Iron metabolism in the erythrophagocytosing kupffer cell. 2581988 - Acute effects of testicular and adrenal cortical blockade on protein synthesis and dihy... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-06-18 |
Journal Detail:
|
Title: Cellular signalling Volume: 20 ISSN: 0898-6568 ISO Abbreviation: Cell. Signal. Publication Date: 2008 Oct |
Date Detail:
|
Created Date: 2008-08-25 Completed Date: 2008-11-14 Revised Date: 2008-11-21 |
Medline Journal Info:
|
Nlm Unique ID: 8904683 Medline TA: Cell Signal Country: England |
Other Details:
|
Languages: eng Pagination: 1780-6 Citation Subset: IM |
Affiliation:
|
Institute of Physiology, University of Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Apoptosis / drug effects* Calcineurin / antagonists & inhibitors, metabolism* Calcium / pharmacology Calpain / antagonists & inhibitors Cytoplasm / drug effects, metabolism Dexamethasone / pharmacology* Drug Synergism Enzyme Activation / drug effects Fura-2 Glucose / pharmacology HSP90 Heat-Shock Proteins / metabolism* Insulin-Secreting Cells / cytology*, drug effects, enzymology* Protein Binding / drug effects Rats Substrate Specificity / drug effects Tacrolimus / pharmacology |
| Chemical | |
Reg. No./Substance:
|
0/HSP90 Heat-Shock Proteins; 109581-93-3/Tacrolimus; 50-02-2/Dexamethasone; 50-99-7/Glucose; 7440-70-2/Calcium; 96314-98-6/Fura-2; EC 3.1.3.16/Calcineurin; EC 3.4.22.-/Calpain |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Vesicular glutamate transporter 3-immunoreactive pericellular baskets ensheath a distinct population...
Next Document: Antimicrobial peptides and self-DNA in autoimmune skin inflammation.