GH modulation of EGF signaling in liver of GHR-KO and PEPCK-bGH transgenic mice.

GONZÁLEZ L; DÍAZ ME; MIQUET JG; SOTELO AI; BARTKE A; TURYN D

Río de Janeiro, Brasil

Congreso; 13th International Congress of Endocrinology; 2008

Epidermal growth factor (EGF) is involved in the pathogenesis and progression of different types of cancer. Receptors from the ErbB family, to which the EGF receptor (EGFR) belongs, can be activated by direct binding of the specific ligand but also by transactivation. Growth hormone (GH) indirectly activates ErbB receptors and control EGFR turnover. Chronically elevated levels of GH have been associated to the progression of cancer. Moreover, GH overexpressing transgenic mice show an increased tendency to develop cancer. OBJETIVE: The objective of the present study was to analyze how GH action condition EGF signaling in liver. METHODOLOGY: To analyze the impact of GH modulation on EGF signaling, transgenic mice overexpressing bovine GH (bGH) and GH receptor knock-out mice (GHR-KO) were used. Transgenic mice, GHR-KO mice and their respective controls were stimulated with EGF or saline, to evaluate basal conditions. Following acute stimulation, mice were killed, livers removed and solubilized. The protein content and level of phosphorylation of molecules involved in EGF signaling were analyzed by Western Blotting. RESULTS: EGFR content decreased in GHR-KO mice. Consequently, EGF induced phosphorylation at Y845, Y992 and Y1068 of EGFR was significantly diminished in GHR-KO mice respect to EGF stimulated normal mice. Akt, Erk1/2, Stat3 and Stat5 phosphorylation was also reduced in GHR-KO mice. On the contrary, EGFR content was increased in transgenic mice overexpressing bGH as well as basal phosphorylation in Y845, Y992 and Y1068. However, EGF-induced phosphorylation of EGFR was not increased in transgenic animals. EGF stimulation caused similar levels of Akt and Erk1/2 phosphorylation in normal and transgenic mice. EGF induction of Stat3 and Stat5 phosphorylation was diminished in transgenic mice. CONCLUSIONS: GH modulates EGF signaling in different ways depending on the hormone action. While abrogation of GH action produces a decrease in EGFR expression and a concomitant decrease on EGF signaling, high GH concentration induces EGFR overexpression but does not result in enhanced EGF signaling. Furthermore, effects differ depending on the signaling pathway analyzed: Akt and Erk1/2 pathways are not affected while Stat3 and Stat5 suffer specific and heterologous desensitization.