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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

T cell receptor signaling inhibits glucocorticoid-induced apoptosis by repressing the SRG3 expression via Ras

Myunggon Ko1, Jiho Jang, Jeongeun Ahn

  • 1School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742.

The Journal of Biological Chemistry
|March 16, 2004
PubMed

Insights

T-cell receptor (TCR) signaling protects immature T cells from glucocorticoid-induced apoptosis by downregulating SRG3 expression via Ras activation, a key mechanism for T-cell survival during development.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • T-cell antigen receptor (TCR) signaling inhibits glucocorticoid (GC)-induced apoptosis in T cells, but the underlying mechanisms remain unclear.
  • SRG3, a homolog of human BAF155, shows inverse correlation with GC sensitivity in T cells and decreases during thymic positive selection.

Purpose of the Study:

  • To elucidate the mechanism by which activated T cells resist GC-induced apoptosis.
  • To investigate the role of TCR signaling and SRG3 in T-cell resistance to GC-mediated apoptosis.

Main Methods:

  • Utilized pharmacological inhibitors to probe signaling pathways (Ras, MEK/ERK, PI3K).
  • Analyzed SRG3 gene expression and promoter activity in primary thymocytes and thymoma cells.
  • Employed site-directed mutagenesis to assess the role of transcription factor binding sites (E proteins, Ets) in the SRG3 promoter.

Main Results:

  • TCR signaling inhibits SRG3 expression through Ras activation, conferring resistance to GC-induced apoptosis in thymocytes and thymoma cells.
  • Ras-mediated SRG3 down-regulation involves MEK/ERK and phosphatidylinositol 3-kinase pathways.
  • TCR signals repress SRG3 transcription by targeting E protein and Ets family transcription factor binding sites in the promoter region.

Conclusions:

  • TCR signaling induces GC desensitization in immature T cells by repressing SRG3 gene expression via Ras activation.
  • The findings reveal a novel regulatory pathway controlling T-cell survival and GC sensitivity during thymic development.

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