Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltex1 by blocking the recruitment of p300 to the SRG3 promoter
Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltex1 by blocking the recruitment of p300 to the SRG3 promoter
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DOI：
10.1038/sj.cdd.4401827
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发表时间：
2006-09-01
影响因子：
12.4
通讯作者：
Seong, R. H.
中科院分区：
文献类型：
--
作者：
Jang, J.;Choi, Y. I.;Seong, R. H.
在未成熟胸腺细胞分化为成熟CD4或CD8单阳性谱系的过程中，一个值得注意的表型变化是获得对糖皮质激素（GC）诱导的细胞凋亡的抗性。我们之前报道过SRG3在确定gc诱导的胸腺细胞凋亡的敏感性方面是至关重要的。我们在这里报道Notch信号通过启动子上的N-box和/或E-box元件下调SRG3的转录激活。RBP-J通过N-box基序抑制SRG3的转录。另一方面，Deltex1竞争性地抑制p300与E-box元件结合的E2A/HEB蛋白的结合，抑制SRG3启动子活性。此外，强制表达Deltex1可以恢复双阳性胸腺细胞的存活，使其免于gc诱导的凋亡。我们的研究结果表明，Notch信号通过Deltex1调控SRG3的表达，使分化的DP胸腺细胞对GCs产生抗性，Deltex1和SRG3可能在DP胸腺细胞成熟过程中发挥重要作用。
One notable phenotypic change during the differentiation of immature thymocytes into either mature CD4 or CD8 singlepositive 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.