title: Mitogenic signaling pathways in the liver of growth hormone (GH)-overexpressing mice during the growth period.
abstract: Growth hormone (GH) is a pleiotropic hormone that triggers STATs, ERK1/2 and Akt signaling, related to cell growth and proliferation. Transgenic mice overexpressing GH present increased body size, with a disproportionate liver enlargement due to hypertrophy and hyperplasia of the hepatocytes. We had described enhanced mitogenic signaling in liver of young adult transgenic mice. We now evaluate the activation of these signaling cascades during the growth period and relate them to the morphological alterations found. Signaling mediators, cell cycle regulators and transcription factors involved in cellular growth in the liver of GH-overexpressing growing mice were assessed by immunoblotting, RT-qPCR and immunohistochemistry. Hepatocyte enlargement can be seen as early as 2-weeks of age in GH-overexpressing animals, although it is more pronounced in young adults. Levels of cell cycle mediators PCNA and cyclin D1, and transcription factor c-Jun increase with age in transgenic mice with no changes in normal mice, whereas c-Myc levels are higher in 2-week-old transgenic animals and cyclin E levels decline with age for both genotypes. STAT3, Akt and GSK3 present higher activation in the adult transgenic mice than in the growing animals, while for c-Src and mTOR, phosphorylation in GH-overexpressing mice is higher than in control siblings at 4 and 9 weeks of age. No significant changes are observed for ERK1/2, neither by age or genotype. Thus, the majority of the mitogenic signaling pathways are gradually up-regulated in the liver of GH-transgenic mice, giving rise to the hepatic morphological changes these mice exhibit.
authors.affiliation: a Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica , Buenos Aires , Argentina.
authors.forename: Carolina S
authors.initials: CS
authors.lastname: Martinez
authors.affiliation: a Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica , Buenos Aires , Argentina.
authors.forename: Verónica G
authors.initials: VG
authors.lastname: Piazza
authors.affiliation: a Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica , Buenos Aires , Argentina.
authors.forename: Lorena
authors.initials: L
authors.lastname: González
authors.affiliation: b Department of Geriatrics (A.B.) , School of Medicine, Southern Illinois University , Springfield , IL , USA.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Fang
authors.affiliation: b Department of Geriatrics (A.B.) , School of Medicine, Southern Illinois University , Springfield , IL , USA.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
authors.affiliation: a Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica , Buenos Aires , Argentina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Turyn
authors.affiliation: a Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica , Buenos Aires , Argentina.
authors.forename: Johanna G
authors.initials: JG
authors.lastname: Miquet
authors.affiliation: a Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica , Buenos Aires , Argentina.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Sotelo
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis; D009929:Organ Size; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013006:Growth Hormone; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Akt/mTOR/GSK3β; ERK1/2; GH-overexpressing mice; Growth hormone; PCNA; STAT3; c-Jun; c-Myc; cell cycle regulators; hepatomegaly; liver