title: Increased sensitivity to GH in liver of Ames dwarf (Prop1df/Prop1df) mice related to diminished CIS abundance.
abstract: To investigate the influence of chronic GH deficiency on GH signaling in vivo, we have analyzed Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT) 5 GH signaling pathway, and its regulation by the suppressors of the cytokine signaling SOCS and by the JAK2-interacting protein SH2-Bbeta, in liver of Ames dwarf (Prop1df/Prop1df) mice, which are severely deficient in GH, prolactin and TSH, and of their normal littermates. Prop1df/Prop1df mice displayed unaltered GH receptor, JAK2 and STAT5a/b protein levels. No significant differences in the basal tyrosine-phosphorylation levels of JAK2 and STAT5a/b were found between both groups of animals. After in vivo administration of a high GH dose (5 microg/g body weight (BW)), the tyrosine-phosphorylation levels of JAK2 and STAT5a/b increased significantly, reaching similar values in normal and dwarf mice. However, after stimulation with lower GH doses (50 and 15 ng/g BW) the tyrosine-phosphorylation level of STAT5a/b was higher in dwarf mice. The protein content of CIS, a SOCS protein that inhibits STAT5 signaling, was approximately 80% lower in dwarf mice liver, while SOCS-2 and SOCS-3 levels were unaltered. The content of SH2-Bbeta, a modulator of JAK2 activity, was reduced by approximately 30% in dwarf mice, although this was associated with normal JAK2 response to a high GH dose. In summary, Prop1df/Prop1df mice display increased hepatic sensitivity to GH, an effect that could be related to the lower abundance of CIS in this tissue. Furthermore, the lower CIS content found in this model of GH deficiency suggests that CIS protein levels are regulated by GH in vivo.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956, 1113, Buenos Aires, Argentina.
authors.forename: J G
authors.initials: JG
authors.lastname: Miquet
authors.forename: A I
authors.initials: AI
authors.lastname: Sotelo
authors.forename: F P
authors.initials: FP
authors.lastname: Dominici
authors.forename: M S
authors.initials: MS
authors.lastname: Bonkowski
authors.forename: A
authors.initials: A
authors.lastname: Bartke
authors.forename: D
authors.initials: D
authors.lastname: Turyn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D013006:Growth Hormone / Q000172:deficiency* / Q000378:metabolism / Q000502:physiology; D017874:Immediate-Early Proteins / Q000032:analysis*; D053614:Janus Kinase 2; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000032:analysis; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D013006:Growth Hormone; D017874:Immediate-Early Proteins; D053614:Janus Kinase 2; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; C115327:Sh2bpsm1 protein, mouse; C507926:Jak2 protein, mouse