T cell receptor signaling inhibits glucocorticoid-induced apoptosis by repressing the SRG3 expression via Ras activation.
Activation of T cell antigen receptor (TCR) signaling inhibits glucocorticoid (GC)-induced apoptosis of T cells. However, the detailed mechanism regarding how activated T cells are protected from GC-induced apoptosis is unclear. Previously, we have shown that the expression level of SRG3, a murine homolog of BAF155 in humans, correlated well with the GC sensitivity of T cells either in vitro or in vivo. Intriguingly, the expression of SRG3 decreased upon positive selection in the thymus. Here we have shown that TCR signaling inhibits the SRG3 expression via Ras activation and thereby renders primary thymocytes and some thymoma cells resistant to GC-mediated apoptosis. By using pharmacological inhibitors, we have shown that Ras-mediated down-regulation of the SRG3 gene expression is mediated by MEK/ERK and phosphatidylinositol 3-kinase pathways. Moreover, TCR signals repressed the SRG3 transcription through the putative binding sites for E proteins and Ets family transcription factors in the proximal region of the SRG3 promoter. Introduction of mutations in these elements rendered the SRG3 promoter immune to the Ras or TCR signals. Taken together, these observations suggest that TCR signals result in GC desensitization in immature T cells by repressing SRG3 gene expression via Ras activation.
Ko
Myunggon
M
School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742.
Jang
Jiho
J
Ahn
Jeongeun
J
Lee
Kyuyoung
K
Chung
Heekyoung
H
Jeon
Sung H
SH
Seong
Rho H
RH
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D001667:Binding, Competitive; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D011725:Pyridines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D005938:Glucocorticoids; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011725:Pyridines; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D003907:Dexamethasone; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one