Identification of CCAAT/enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene.
The prototypical second messenger cAMP 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 signaling-3 (SOCS-3), a negative regulator of IL-6 receptor signaling. We have determined previously that SOCS-3 induction by cAMP occurs independently of cAMP-dependent protein kinase, instead requiring the recently identified cAMP sensor exchange protein activated by cAMP 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 increased C/EBP DNA binding activity and recruitment of C/EBPbeta to the SOCS-3 promoter. Secondly, knockdown of C/EBPbeta and -delta isoforms abolished both SOCS-3 induction and inhibition of IL-6 signaling in response to cAMP. Thirdly, overexpression of C/EBPalpha, -beta, or -delta potentiated EPAC-mediated accumulation of SOCS-3. Finally, these effects were not restricted to human umbilical vein endothelial cells, because similar phenomena were observed in murine embryonic fibroblasts in which C/EBPbeta or delta had been deleted. In summary, our findings constitute the first description of an EPAC-C/EBP pathway that can control cAMP-mediated changes in gene expression independently of protein kinase A.
Yarwood
Stephen J
SJ
Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Davidson Bldg., Glasgow G12 8QQ, United Kingdom. S.Yarwood@bio.gla.ac.uk
Borland
Gillian
G
Sands
William A
WA
Palmer
Timothy M
TM
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D020033:Protein Isoforms; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology
D022762:CCAAT-Enhancer-Binding Proteins; D015850:Interleukin-6; D020033:Protein Isoforms; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases