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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0002v1 198/2/317    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Miquet, J. Articles by Sotelo, A. PubMed PubMed Citation Articles by Miquet, J. Articles by Sotelo, A.

J Miquet, Instituto de Quimica y Fisicoquimica Biologicas (UBA-CONICET), Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina
L Gonzalez, Instituto de Quimica y Fisicoquimica Biologicas (UBA-CONICET), Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina
M Matos, Instituto de Quimica y Fisicoquimica Biologicas (UBA-CONICET), Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina
C Hansen, Department of Internal medicine, Southern Illinois University School of Medicine, Springfield, United States
A Louis, Southern Illinois University, Springfield, United States
A Bartke, Department of Internal medicine, Southern Illinois University School of Medicine, Springfield, United States
D Turyn, Instituto de Quimica y Fisicoquimica Biologicas (UBA-CONICET), Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina
A Sotelo, Buenos Aires, Argentina

Correspondence: Johanna Miquet, Email: miquetjg{at}yahoo.com

Abstract

Chronically elevated levels of growth hormone in GH-transgenic mice result in accelerated growth and increased adult body weight. We have previously described that the GH-induced JAK2/STAT5 signaling pathway is desensitized in the liver of transgenic mice overexpressing GH. However, these animals present increased circulating IGF-I levels, increased hepatic GHR expression and liver organomegaly due to hypertrophy and hyperplasia, which frequently progress to hepatomas as the animals age, indicating that action of GH on the liver is not prevented. In the present study, we have evaluated other GH signaling pathways that could be activated in the liver of GH transgenic mice. Upon GH administration, normal mice showed an important increment in STAT3 phosphorylation level, but transgenic mice did not respond to acute GH stimulation. However, STAT3 was constitutively phosphorylated in transgenic mice, whereas its protein content was not increased. GH transgenic mice showed overexpression of c-Src, accompanied by an elevation of its activity. Other signaling mediators including FAK, EGFR, Erk, Akt and mTOR displayed elevated protein and basal phosphorylation levels in these animals. Thus, GH-overexpressing transgenic mice exhibit hepatic upregulation of signaling mediators related to cell proliferation, survival and migration. The upregulation of these proteins may represent GH signaling pathways that are constitutively activated in the presence of dramatically elevated GH levels throughout life. These molecular alterations could be implicated in the pathological alterations observed in the liver of GH transgenic mice.