title: The regulation of the mitochondrial apoptotic pathway by glucocorticoid receptor in collaboration with Bcl-2 family proteins in developing T cells.
abstract: Glucocorticoids (GC) are important in the regulation of selection and apoptosis of CD4+CD8+double-positive (DP) thymocytes. The pronounced GC-sensitivity of DP thymocytes, observed earlier, might be due to the combination of classical (genomic) and alternative (non-genomic) glucocorticoid receptor (GR) signaling events modifying activation or apoptotic pathways. In particular, the previously demonstrated mitochondrial translocation of activated GR in DP thymocytes offered a fascinating explanation for their pronounced GC-induced apoptosis sensitivity. However, the fine molecular details how the mitochondrial translocation of GR might regulate apoptosis remained unclear. Therefore, in the present study, we intended to examine which apoptotic pathways could be involved in GC-induced thymocyte apoptosis. Furthermore we investigated the potential relationship between the GR and Bcl-2 proteins. Using an in vitro test system, thymocytes from 4-week-old BALB/c mice, were treated with the GC-analogue dexamethasone (DX). Bax accumulated in mitochondria upon DX treatment. Mitochondrial GR showed association with members of the Bcl-2 family: Bak, Bim, Bcl-xL. Elevated Cytochrome C, and active caspase-3, -8, and -9 levels were detected in thymocytes after DX treatment. These results support the hypothesis that in early phases of GC-induced thymocyte apoptosis, the mitochondrial pathway plays a crucial role, confirmed by the release of Cytochrome C and the activation of caspase-9. The activation of caspase-8 was presumably due to cross-talk between apoptotic signaling pathways. We propose that the GC-induced mitochondrial accumulation of Bax and the interaction between the GR and Bim, Bcl-xLand Bak could play a role in the regulation of thymocyte apoptosis.
authors.affiliation: Department of Immunology and Biotechnology, University of Pécs Medical Center, Szigeti út. 12., Pecs, 7624, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Prenek
authors.affiliation: Department of Immunology and Biotechnology, University of Pécs Medical Center, Szigeti út. 12., Pecs, 7624, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Boldizsár
authors.affiliation: Department of Immunology and Biotechnology, University of Pécs Medical Center, Szigeti út. 12., Pecs, 7624, Hungary.
authors.forename: Réka
authors.initials: R
authors.lastname: Kugyelka
authors.affiliation: Department of Immunology and Biotechnology, University of Pécs Medical Center, Szigeti út. 12., Pecs, 7624, Hungary.
authors.forename: Emese
authors.initials: E
authors.lastname: Ugor
authors.affiliation: Department of Medical Biology, University of Pécs Medical School, Szigeti út. 12., Pecs, 7624, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Berta
authors.affiliation: Department of Immunology and Biotechnology, University of Pécs Medical Center, Szigeti út. 12., Pecs, 7624, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Németh
authors.affiliation: Department of Immunology and Biotechnology, University of Pécs Medical Center, Szigeti út. 12., Pecs, 7624, Hungary. berki.timea@pte.hu.
authors.forename: Timea
authors.initials: T
authors.lastname: Berki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D020169:Caspases / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D060168:Thymocytes / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D005938:Glucocorticoids; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases
keywords: Bcl-2 proteins; Glucocorticoid hormone; Glucocorticoid receptor; Mitochondria; Non-genomic pathway; Thymocyte apoptosis