Transgenic mice overexpressing GH exhibit hepatic upregulation of GH-signaling mediators involved in cell proliferation.
Chronically elevated levels of GH 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 focal adhesion kinase, epidermal growth factor receptor, Erk, Akt, and mammalian target of rapamycin 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.
Miquet
Johanna G
JG
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956, C1113AAD Buenos Aires, Argentina.
González
Lorena
L
Matos
Marina N
MN
Hansen
Christina E
CE
Louis
Audreen
A
Bartke
Andrzej
A
Turyn
Daniel
D
Sotelo
Ana I
AI
D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D013006:Growth Hormone / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D047468:Immunoprecipitation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000378:metabolism; D009929:Organ Size; D010766:Phosphorylation / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D019061:src-Family Kinases / Q000378:metabolism
D002352:Carrier Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D013006:Growth Hormone; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases