Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltex1 by blocking the recruitment of p300 to the SRG3 promoter

Cell Death Differ. 2006 Sep;13(9):1495-505. doi: 10.1038/sj.cdd.4401827. Epub 2005 Dec 9.

Abstract

One notable phenotypic change during the differentiation of immature thymocytes into either mature CD4 or CD8 single-positive lineages is the acquisition of a resistance to glucocorticoid (GC)-induced apoptosis. We have previously reported that SRG3 is critical in determining the sensitivity for the GC-induced apoptosis in developing thymocytes. We report here that Notch signaling downregulates the transcriptional activation of SRG3 through N-box and/or E-box elements on its promoter. RBP-J represses SRG3 transcription through the N-box motif. On the other hand, Deltex1 competitively inhibits the binding of p300 to E2A/HEB protein bound to the E-box elements and represses the SRG3 promoter activity. Moreover, enforced expression of Deltex1 restored double-positive (DP) thymocyte survival from the GC-induced apoptosis. Our results suggest that Notch signaling confers differentiating DP thymocytes resistance to GCs by regulating the SRG3 expression through Deltex1, and that Deltex1 and SRG3 may play a significant role during DP thymocyte maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Differentiation
  • Cell Line
  • Cell Survival / drug effects
  • DNA-Binding Proteins / metabolism*
  • E1A-Associated p300 Protein / metabolism*
  • Glucocorticoids / pharmacology*
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Oncogene Proteins, Fusion / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Receptor, Notch1 / physiology*
  • Repressor Proteins / genetics*
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / physiology*
  • Trans-Activators / genetics*
  • Transcriptional Activation
  • Ubiquitin-Protein Ligases

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • E2a-Hlf fusion protein, mouse
  • Glucocorticoids
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Notch1 protein, mouse
  • Oncogene Proteins, Fusion
  • RBPJ protein, human
  • Receptor, Notch1
  • Repressor Proteins
  • Tcf12 protein, mouse
  • Trans-Activators
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
  • Dtx1 protein, mouse
  • Ubiquitin-Protein Ligases