Yarwood, S.J., Borland, G., Sands, W.A. and Palmer, T.M. (2008) Identification of CCAAT/Enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene. Journal of Biological Chemistry, 283(11), pp. 6843-6853. (doi: 10.1074/jbc.M710342200)
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Abstract
The prototypical second messenger cyclic AMP is a key regulator of immune and inflammatory responses. Its ability to inhibit interleukin (IL)-6 responses is due to induction of "suppressor of cytokine signalling-3" (SOCS-3), a negative regulator of IL-6 receptor signaling. We have determined previously that SOCS-3 induction by cyclic AMP occurs independently of cyclic AMP-dependent protein kinase (PKA), instead requiring the recently identified cyclic AMP sensor "exchange protein activated by cyclic AMP 1" (EPAC1). Here we present evidence to suggest that the C/EBP family of transcription factors link EPAC1 activation to SOCS-3 induction. Firstly, selective activation of EPAC in human umbilical vein endothelial cells (HUVECs) increased C/EBP DNA binding activity and recruitment of C/EBP[beta] to the SOCS-3 promoter. Secondly, knockdown of C/EBP[beta] and [delta] isoforms abolished both SOCS-3 induction and inhibition of IL-6 signaling in response to cyclic AMP. Thirdly, overexpression of C/EBP[alpha], [beta] or [delta] potentiated EPAC-mediated accumulation of SOCS-3. Finally, these effects were not restricted to HUVECs, as similar phenomena were observed in murine embryonic fibroblasts in which C/EBP[beta] or [delta] had been deleted. In summary, our findings constitute the first description of an EPAC-C/EBP pathway that can control cyclic AMP-mediated changes in gene expression independently of PKA
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Yarwood, Dr Stephen and Borland, Dr Gillian and Sands, Dr William and Palmer, Dr Timothy |
| Authors: | Yarwood, S.J., Borland, G., Sands, W.A., and Palmer, T.M. |
| Subjects: | Q Science > QD Chemistry Q Science > QH Natural history > QH345 Biochemistry |
| College/School: | College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences |
| Journal Name: | Journal of Biological Chemistry |
| Journal Abbr.: | J Biol Chem. |
| Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
| ISSN: | 0021-9258 |
| ISSN (Online): | 1083-351X |
| Published Online: | 14 January 2008 |
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