Abstract
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. Rcan1 encodes two major transcripts, Rcan1-1 and Rcan1-4, resulting from differential promoter use and first exon choice. We found that a single injection of GH increased the levels of Rcan1-4 mRNA and RCAN1-4 protein transiently, but did not increase Rcan1-1 mRNA in HPX rat liver. Then the molecular mechanism of GH to induce Rcan1-4 transcription was examined in rat hepatoma H4IIE cells. Experiments using inhibitors suggested that c-JUN N-terminal kinase was required for the induction of Rcan1-4 mRNA by GH. GH increased the levels of phosphorylated c-JUN protein and c-Jun mRNA in HPX rat liver. The luciferase and electrophoretic mobility shift assays showed that c-JUN upregulated Rcan1-4 mRNA by binding to the cAMP-responsive element in the upstream of Rcan1 exon 4. These results indicate that GH activates c-JUN to affect the activity of calcineurin by the induction of Rcan1-4 in rat liver.
Highlights
Growth hormone (GH) is a critical hormone for growth and plays a role in numerous important physiological processes, such as lipolysis, gluconeogenesis, and protein synthesis [1, 2]
To identify the clones that were really upregulated by GH, they were analyzed by virtual northern blot and 8 clones that were upregulated by GH were sequenced (S1 Table). mRNA levels of these genes were further determined by northern blotting to confirm that GH regulated the expression of these genes
We found that the levels of regulator of calcineurin 1 (Rcan1), Xbp1, Nampt, and Leap2 mRNAs were much higher at 1 h after GH injection than those after vehicle injection (Fig 1A)
Summary
Growth hormone (GH) is a critical hormone for growth and plays a role in numerous important physiological processes, such as lipolysis, gluconeogenesis, and protein synthesis [1, 2]. The effects of GH on transcription in the liver, where GH receptors are abundantly expressed, have been extensively studied [3, 4]. The actions of GH are mediated directly by its own receptor and indirectly by production of insulin-like growth factor 1 (IGF-1) [5]. Because many unknown genes could be regulated by GH, we tried to identify new genes whose transcription was induced by GH in the liver of hypophysectomized (HPX) rats using the suppression subtractive hybridization (SSH) technique [6]. We found that GH increased regulator of calcineurin 1 (Rcan1) mRNA in HPX rat liver.
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