E2A/HEB and Id3 proteins control the sensitivity to glucocorticoid-induced apoptosis in thymocytes by regulating the SRG3 expression.
The E protein family transcription factors encoded by the E2A and HEB genes are known to play critical roles in the coordinate regulation of lymphocyte development. Previous studies have shown that T cell receptor (TCR) signals rapidly induce Id3, a dominant negative antagonist of E2A activity and allow thymocytes to survive selection events in the thymus. Here we show that SRG3 acts as a novel downstream target of E2A/HeLa E box-binding (HEB) complex and modulates glucocorticoid (GC) susceptibility in thymocytes in response to TCR signals. We have identified a putative E box element in the SRG3 promoter that is required for optimal promoter activity. The transcription factors E2A and HEB specifically associate with the E box element. Moreover, E2A-HEB heterodimers cooperated to activate SRG3 transcription, which was inhibited by the expression of Id proteins. TCR-mediated signals rapidly induced Id3 via MEK/ERK activation and thereby kept the E2A/HEB complex from binding to the E box element in the SRG3 promoter. Retroviral transduction of Id3 also repressed the SRG3 expression by inhibiting the E box binding activity of the E2A/HEB complex. Intriguingly, enforced Id3 expression conferred thymocyte resistance to GCs, which could be overcome by the overexpression of SRG3. Taken together, these results suggest that Id3 may enhance the viability of immature thymocytes by at least rendering them resistant to GCs through SRG3 down-regulation.
Ko
Myunggon
M
School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742.
Ahn
Jeongeun
J
Lee
Changjin
C
Chung
Heekyoung
H
Jeon
Sung H
SH
Chung
Hee-Y
HY
Seong
Rho H
RH
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D015152:Blotting, Northern; D016923:Cell Death; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005434:Flow Cytometry; D017930:Genes, Reporter; D005822:Genetic Vectors; D005938:Glucocorticoids / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D051796:Inhibitor of Differentiation Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000166:cytology*; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D005938:Glucocorticoids; D049452:Green Fluorescent Proteins; D051796:Inhibitor of Differentiation Proteins; D008164:Luminescent Proteins; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C407909:TCF3 protein, human; C075640:ID3 protein, human