Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells.
Leptin inhibits insulin secretion and preproinsulin gene expression in pancreatic beta-cells, but signal transduction pathways and molecular mechanisms underlying this effect are poorly characterized. In this study, we analyzed leptin-mediated signal transduction and preproinsulin gene regulation at the molecular level in pancreatic beta-cells. Leptin stimulation led to janus kinase (JAK)2-dependent phosphorylation and nuclear translocation of the transcription factors signal transducer and activator of transcription (STAT)3 and STAT5b in INS-1 beta-cells. Leptin also induced mRNA expression of the JAK-STAT inhibitor suppressor of cytokine signaling (SOCS)3 in INS-1 beta-cells and human pancreatic islets in vitro and in pancreatic islets of ob/ob mice in vivo. Transcriptional activation of the rat SOCS3 promoter by leptin was observed with concomitant leptin-induced STAT3 and STAT5b DNA binding to specific promoter regions. Unexpectedly, SOCS3 inhibited both basal and STAT3/5b-dependent rat preproinsulin 1 gene promoter activity in INS-1 cells. These results suggest that SOCS3 represents a transcriptional inhibitor of preproinsulin gene expression, which is induced by leptin through JAK-STAT3/5b signaling in pancreatic beta-cells. In conclusion, although SOCS3 is believed to be a negative feedback regulator of JAK-STAT signaling, our findings suggest involvement of SOCS3 in a direct gene regulatory pathway downstream of leptin-activated JAK-STAT signaling in pancreatic beta-cells.
Laubner
Katharina
K
Division of Metabolism, Endocrinology, and Molecular Medicine, Medizinische Klinik und Poliklinik II, University of Würzburg, Klinikstrasse 6-8, 97070 Würzburg, Germany.
Kieffer
Timothy J
TJ
Lam
Ni T
NT
Niu
Xinjie
X
Jakob
Franz
F
Seufert
Jochen
J
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007150:Immunohistochemistry; D007328:Insulin; D007340:Insulinoma; D007515:Islets of Langerhans / Q000502:physiology*; D020738:Leptin / Q000494:pharmacology*; D010190:Pancreatic Neoplasms; D011384:Proinsulin / Q000037:antagonists & inhibitors / Q000235:genetics*; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000235:genetics*; D012333:RNA, Messenger; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*
D017931:DNA Primers; D007328:Insulin; D020738:Leptin; D011498:Protein Precursors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; C494097:Stat5b protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C013737:preproinsulin; D011384:Proinsulin