期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 26, 页码 17391-17403出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.015370
关键词
-
资金
- Biotechnology and Biological Sciences Research Council [BB/D015324/1]
- British Heart Foundation [PG/08/125]
- BBSRC [BB/D015324/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D015324/1] Funding Source: researchfish
- British Heart Foundation [PG/08/125/26415] Funding Source: researchfish
We recently found that induction of the anti-inflammatory SOCS-3 gene by cyclic AMP occurs through novel cyclic AMP-dependent protein kinase-independent mechanisms involving activation of CCAAT/enhancer-binding protein (C/EBP) transcription factors, notably C/EBP beta, by the cyclic AMP GEF EPAC1 and the Rap1 GTPase. In this study we show that down-regulation of phospholipase (PL) C epsilon with small interfering RNA or blockade of PLC activity with chemical inhibitors ablates exchange protein directly activated by cyclic AMP (EPAC)-dependent induction of SOCS-3 in COS1 cells. Consistent with this, stimulation of cells with 1-oleoyl-2-acetyl-sn-glycerol and phorbol 12-myristate 13-acetate, both cell-permeable analogues of the PLC product diacylglycerol, are sufficient to induce SOCS-3 expression in a Ca2+-dependent manner. Moreover, the diacylglycerol- and Ca2+-dependent protein kinase C (PKC) isoform PKC alpha becomes activated following cyclic AMP elevation or EPAC stimulation. Conversely, down-regulation of PKC activity with chemical inhibitors or small interfering RNA-mediated depletion of PKC alpha or -delta blocks EPAC-dependent SOCS-3 induction. Using the MEK inhibitor U0126, we found that activation of ERK MAPKs is essential for SOCS-3 induction by either cyclic AMP or PKC. C/EBP beta is known to be phosphorylated and activated by ERK. Accordingly, we found ERK activation to be essential for cyclic AMP-dependent C/EBP activation and C/EBP beta-dependent SOCS-3 induction by cyclic AMP and PKC. Moreover, overexpression of a mutant form of C/EBP beta (T235A), which lacks the ERK phosphorylation site, blocks SOCS-3 induction by cyclic AMP and PKC in a dominant-negative manner. Together, these results indicate that EPAC mediates novel regulatory cross-talk between the cyclic AMP and PKC signaling pathways leading to ERK- and C/EBP beta-dependent induction of the SOCS-3 gene.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据