The Roles of Ets-1 in IL-2 Regulation
Date Issued
2013
Date
2013
Author(s)
Tsao, Hsiao-Wei
Abstract
Ets-1, the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 in murine and human T cells. Although IL-2 is a well characterized cytokine, how Ets-1 regulates the expression of IL-2 remains unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by murine CD8+ T cells and primary human T helper (Th) cells. We also observed an elevated Blimp-1 expression in Ets-1 KO T cells. Although Blimp-1 plays as a suppressor for IL-2, our data indicated that Blimp-1 is not responsible for the impaired IL-2 production in Ets-1 KO cells. The defects we observed in Ets-1-deficient cells cannot be rescued by Blimp-1 deficiency in Ets-1 KO cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) through multiple domains and is required for the recruitment of NFAT to the IL-2 promoter. In resting Th cells, Ets-1 is located both in nucleus and cytoplasm. When receiving calcium dependent signals from T cell receptors (TCR), nuclear Ets-1 starts to exit the nucleus and competes with NFAT proteins for binding to protein components of NRON (non-coding RNA repressor of NFAT) complex. NRON complex serves as a cytoplasmic trap for phosphorylated NFAT proteins in cytoplasm and this competition results in the release of NFAT from the complex. Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. We also found that the nuclear resident Ets-1 can interact with NFAT proteins to facilitate the transcription activity of NFAT in nucleus. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT. To the best of our knowledge, Ets-1 is the first transcription factor that is known to interact with NRON complex and facilitate nuclear entry of NFAT proteins.
Subjects
介白素二
基因調控
Type
thesis
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