Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltex1 by blocking the recruitment of p300 to the SRG3 promoter.
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.
Jang
J
J
Department of Biological Sciences, Institute of Molecular Biology of Genetics, and Center for Functional Cellulomics, Seoul National University, Seoul 151-742, Korea.
Choi
Y I
YI
Choi
J
J
Lee
K Y
KY
Chung
H
H
Jeon
S H
SH
Seong
R H
RH
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases
D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein; D005938:Glucocorticoids; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D015514:Oncogene Proteins, Fusion; D051881:Receptor, Notch1; D012097:Repressor Proteins; D015534:Trans-Activators; D044767:Ubiquitin-Protein Ligases; C489626:E2a-Hlf fusion protein, mouse; C497762:Notch1 protein, mouse; C497570:RBPJ protein, human; C489532:Tcf12 protein, mouse; C494361:Ep300 protein, mouse; C104035:Dtx1 protein, mouse