Growth hormone increases regulator of calcineurin 1-4 (Rcan1-4) mRNA through c-JUN in rat liver

Growth hormone (GH) activates multiple signal transduction pathways. To investigate these pathways, we identified novel genes whose transcription was induced by GH in the liver of hypophysectomized (HPX) rats using the suppression subtractive hybridization technique. We found that regulator of calcineurin 1 (Rcan1) mRNA was upregulated by GH administration. RCAN1 regulates the activity of calcineurin, a Ca/calmodulin-dependent phosphatase.Rcan1encodes two major transcripts,Rcan1-1andRcan1-4, resulting from differential promoter use and first exon choice. We found that a single injection of GH increased the levels ofRcan1-4mRNA and RCAN1-4 protein transiently, but did not increaseRcan1-1mRNA in HPX rat liver. Then the molecular mechanism of GH to induceRcan1-4transcription was examined in rat hepatoma H4IIE cells. Experiments using inhibitors suggested that c-JUN N-terminal kinase was required for the induction ofRcan1-4mRNA by GH. GH increased the levels of phosphorylated c-JUN protein andc-JunmRNA in HPX rat liver. The luciferase and electrophoretic mobility shift assays showed that c-JUN upregulatedRcan1-4mRNA by binding to the cAMP-responsive element in the upstream ofRcan1exon 4. These results indicate that GH activates c-JUN to affect the activity of calcineurin by the induction ofRcan1-4in rat liver.