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The Effect of Suppressor of Cytokine Signaling 3 on GH Signaling in ß-Cells

Steno Diabetes Center (S.G.R., A.E.K., N.B.), DK-2820 Gentofte, Denmark; and Signal Transduction (S.G.R., J.A.H., K.L., N.B.), Novo Nordisk A/S, DK-2880 Bagsværd, Denmark

Address all correspondence and requests for reprints to: Nils Billestrup, Steno Diabetes Center, Niels Steensensvej 6, DK-2820 Gentofte, Denmark. E-mail: nbil{at}novonordisk.com.

GH is an important regulator of cell growth and metabolism. In the pancreas, GH stimulates mitogenesis as well as insulin production in ß-cells. The cellular effects of GH are exerted mainly through activation of the Janus kinase-signal transducer and activator of transcription (STAT) pathway. Recently it has been found that suppressors of cytokine signaling (SOCS) proteins are able to inhibit GH-induced signal transduction. In the present study, the role of SOCS-3 in GH signaling was investigated in the pancreatic ß-cell lines RIN-5AH and INS-1 by means of inducible expression systems. Via stable transfection of the ß-cell lines with plasmids expressing SOCS-3 under the control of an inducible promoter, a time- and dose-dependent expression of SOCS-3 in the cells was obtained. EMSA showed that SOCS-3 is able to inhibit GH-induced DNA binding of both STAT3 and STAT5 in RIN-5AH cells. Furthermore, using Northern blot analysis it was shown that SOCS-3 can completely inhibit GH-induced insulin production in these cells. Finally, 5-bromodeoxyuridine incorporation followed by fluorescence-activated cell sorting analysis showed that SOCS-3 inhibits GH-induced proliferation of INS-1 cells. These findings support the hypothesis that SOCS-3 is a major regulator of GH signaling in insulin-producing cells.

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