Growth hormone (GH)-transgenic mice exhibit GH-STAT5 insensitivity associated with up-regulation of negative signaling modulators

MARTINEZ CS, PIAZZA V, MIQUET JG, RAMIREZ M, BECU-VILLALOBOS D, BARTKE A, TURYN D, SOTELO AI.

Harrogate

Congreso; British Endocrine Society (BES); 2012

Society for Endocrinology

JAK2/STAT5 is the principal growth hormone (GH) signaling pathway related to body growth. It is positively regulated by glucocorticoid receptor (GR) and hepatocyte nuclear factor 1 (HNF-1) and downregulated by activation of tyrosine-phosphatases SHP-1,-2 and PTP-1B, and by GH-induction of suppressors of cytokine signaling (CIS/SOCS) that block GHR or JAK2, and promote internalization/degradation of signaling complexes. This pathway is desensitized in liver of adult transgenic mice expressing bovine GH under control of PEPCK promoter; however, these mice exhibit accelerated growth after weaning and increased adult body size. Therefore, the aim of this work was to assess if GH can activate STAT5 during the growth period and if signaling modulators participate in age-related changes in GH sensitivity in these animals. GH transgenic mice (Tg) and normal siblings (N) 2, 4 and 9 weeks old received an acute GH stimulus to evaluate liver STAT5a/b activation by Western-blotting. Modulators content and gene expression were assayed by Western-blotting and real time RT-PCR. STAT5 phosphorylation is higher in GH-stimulated normal mice at every age studied (P<0.001) than in transgenic animals; moreover, basal STAT5-phosphorylation is similar in N and Tg mice despite Tg animals having elevated circulating GH levels. GR content is equivalent in N and Tg mice while HNF-1 displays higher abundance in transgenic animals (P<0.05). SHP-1 and -2 present no genotype difference at any age, PTP-1B and CIS levels are higher in Tg mice at all ages (P<0.05). SOCS-2 and -3 protein content is diminished while mRNA levels are higher in Tg mice (P<0.05), which suggests that these suppressors are being actively degraded. GH-overexpressing mice have the main GH signaling pathway related to body growth, JAK2/STAT5, desensitized at all ages studied. This could be related to GH-induced expression of suppressors that may contribute to pathway down-regulation by promoting degradation of the signaling complex.