Regulation of suppressor of cytokine signaling 3 (SOC3) by growth hormone in pro-B cells.
Suppressor of cytokine signaling 3 (SOCS3) is expressed by lymphoid cells and can modulate the sensitivity of these cells to cytokine stimulation through inhibition of Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathways. This study employed a mouse pro-B cell line expressing the human GH receptor (BaF/3-GHR), to elucidate the signal transduction pathways used by GH to elicit SOCS3 expression. GH treatment of these cells caused a rapid, dose-dependent increase in SOCS3 mRNA expression, which was independent of de novo protein synthesis. As expected, GH treatment increased JAK-dependent STAT5 tyrosine phosphorylation, which bound to the proximal STAT response element (pSRE) on the SOCS3 promoter. This process appeared to involve STAT5b, rather than STAT5a. In addition, GH activation of the SOCS3 promoter required a nearby activator protein (AP) 1/cAMP response element (CRE), which bound cAMP response element binding protein, c-Fos, and c-Jun. Moreover, inhibitors of p38 MAPK and c-Jun N-terminal kinase prevented GH-stimulation of SOCS3 mRNA expression in these cells, suggesting a role for these kinases in SOCS3 transcription. Importantly, GH stimulation increased binding of FOXO3a to the SOCS3 promoter at a site overlapping the AP1/CRE response element, and overexpression of FOXO3a in these cells augmented SOCS3 promoter activation. In addition, we show a direct interaction between FOXO3a and STAT5 in these cells, which may provide a link between STAT5 and the AP1 transcription factors on the SOCS3 promoter. We conclude that regulation of SOCS3 expression by GH in a pro-B cell involves not only the pSRE, but also a transcriptionally active complex involving cAMP response element binding protein/c-Fos/c-Jun and FOXO3a. This study has implications for cytokine regulation of SOCS gene expression in lymphoid cells.
Barclay
Johanna L
JL
School of Biomedical Sciences, University of Queensland, Queensland 4072, Australia.
Anderson
Stephen T
ST
Waters
Michael J
MJ
Curlewis
Jon D
JD
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D001483:Base Sequence; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020862:GC Rich Sequence; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018808:Transcription Factor AP-1; D013006:Growth Hormone; D053612:Janus Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases