Submitted on February 11, 2008
Accepted on May 21, 2008
Somatostatin inhibits hepatic growth hormone receptor and insulin-like growth factor-1 mRNA expression by activating the ERK and PI3K signaling pathways
Alison L Hagemeister1 and Mark A. Sheridan2*
1 Biological Sciences, North Dakota State University, Fargo, North Dakota, United States
2 Department of Biological Sciences, North Dakota State University, Fargo, United States
* To whom correspondence should be addressed. E-mail: mark.sheridan{at}ndsu.edu.
Previously, we reported that somatostatins (SS) inhibit organismal growth by reducing hepatic growth hormone (GH) sensitivity and by inhibiting insulin-like growth factor-1 (IGF-I) production. In this study, we used hepatocytes isolated from rainbow trout to elucidate the mechanism(s) associated with the extrapituitary growth-inhibiting actions of SS. SS-14, a predominant SS isoform, stimulated tyrosine phosphorylation of several endogenous proteins, including extracellular signal-regulated kinase (ERK), a member the mitogen-activated protein kinase (MAPK) family, and protein kinase B (Akt), a downstream target of phosphatidylinositol 3-kinase (PI3K). SS-14 specifically stimulated the phosphorylation of both ERK 1/2 and Akt in a concentration-dependant fashion. This activation occurred within 5-15 minutes, then subsided after 1 hour. The ERK inhibitor, U0126, retarded SS-14-stimulated phosphorylation of ERK 1/2, whereas the PI3K inhibitor, LY294002, blocked SS-14-stimulated phosphorylation of Akt. SS-14-inhibited expression of GH receptor (GHR) mRNA was blocked by U0126 but not by LY294002. By contrast, U1026 had no effect on SS-14 inhibition of GH-stimulated IGF-1 mRNA expression, whereas LY294002 partially blocked the inhibition of GH-stimulated IGF-1 mRNA expression by SS-14. These results indicate that SS-14-inhibited GHR expression is mediated by the ERK signaling pathway and that the PI3K/Akt pathway mediates, at least in part, SS-14 inhibition of GH-stimulated IGF-1 expression.
