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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Basic-Leucine Zipper Transcription Factors / metabolism
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Cell Differentiation
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Cell Line
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Cell Survival / drug effects
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DNA-Binding Proteins / metabolism*
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E1A-Associated p300 Protein / metabolism*
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Glucocorticoids / pharmacology*
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Humans
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
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Mice
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Mice, Inbred C57BL
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Mutation
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Oncogene Proteins, Fusion / metabolism
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Promoter Regions, Genetic
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Protein Binding
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Receptor, Notch1 / physiology*
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Repressor Proteins / genetics*
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Signal Transduction
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / physiology*
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Trans-Activators / genetics*
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Transcriptional Activation
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Ubiquitin-Protein Ligases
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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E2a-Hlf fusion protein, mouse
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Glucocorticoids
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Immunoglobulin J Recombination Signal Sequence-Binding Protein
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Notch1 protein, mouse
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Oncogene Proteins, Fusion
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RBPJ protein, human
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Receptor, Notch1
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Repressor Proteins
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Tcf12 protein, mouse
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Trans-Activators
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E1A-Associated p300 Protein
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Ep300 protein, mouse
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Dtx1 protein, mouse
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Ubiquitin-Protein Ligases