کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1991805 | 1541030 | 2011 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Macromolecular synthesis inhibitors perturb glucocorticoid receptor trafficking Macromolecular synthesis inhibitors perturb glucocorticoid receptor trafficking](/preview/png/1991805.png)
The ability of inhibitors of transcription and translation to prevent glucocorticoid-induced apoptosis has been interpreted to indicate that the cell death machinery requires de novo protein synthesis. The transcriptional inhibitors actinomycin D (Act D) and DRB as well as the translational inhibitors CHX and puromycin inhibited early loss of mitochondrial membrane integrity in a dose-dependent manner. This effect was not observed with the transcriptional inhibitor α-amanitin suggesting they may have additional effects. Their role in the glucocorticoid receptor (GR) intracellular trafficking was therefore investigated. Here, we show that Act D and CHX reduced glucocorticoid binding, GR turnover and impaired GR nuclear translocation. We performed the same experiments in different thymocyte subpopulations of Balb/c mice. At the highest dose tested, actinomycin D and cycloheximide abolished glucocorticoid-induced cell death of CD4+CD8+ and CD4+CD8−. In all subsets, Act D, DRB, as well as CHX and puromycin prevented receptor nuclear translocation, indicating a general alteration of GR trafficking. Overall, our data support a direct effect of macromolecular inhibitors on GR activation and trafficking. Finally, direct alterations of the functional properties of the glucocorticoid receptor might be responsible for cell death prevention by actinomycin D, DRB, cycloheximide and puromycin.
► Act D, cycloheximide, DRB and puromycin, but not α-amanitin, inhibit corticoid-induced apoptosis.
► Act D and cycloheximide perturb GR proteasomal degradation, binding and nuclear trafficking.
► Act D and cycloheximide inhibit GR trafficking in thymocytes, splenocytes but not carcinoma cells.
► The four inhibitors inhibit corticoid-induced cell death of CD4+CD8+ and CD4+CD8− thymocytes.
► The four inhibitors inhibit liganded GR trafficking in all thymocytes subsets.
Journal: The Journal of Steroid Biochemistry and Molecular Biology - Volume 126, Issues 3–5, September 2011, Pages 104–112