title: Desensitization of the JAK2/STAT5 GH signaling pathway associated with increased CIS protein content in liver of pregnant mice.
abstract: Chronic exposure to growth hormone (GH) was related to the desensitization of the JAK2/STAT5 signaling pathway in liver, as demonstrated in cells, female rats, and transgenic mice overexpressing GH. The cytokine-induced suppressor (CIS) is considered a major mediator of this desensitization. Pregnancy is accompanied by an increment in GH circulating levels, which were reported to be associated with hepatic GH resistance, although the molecular mechanisms involved in this resistance are not clearly elucidated. We thus evaluated the JAK2/STAT5b signaling pathway and its regulation by the suppressors of cytokine signaling (SOCS)/CIS family and the JAK2-interacting protein SH2-Bbeta in pregnant mouse liver, a model with physiological prolonged exposure to high GH levels. Basal tyrosyl phosphorylation levels of JAK2 and STAT5b in pregnant mice were similar to values obtained for virgin animals, in spite of the important increment of GH they exhibit. Moreover, these signaling mediators were not phosphorylated upon GH stimulation in pregnant mice. A 3.3-fold increase of CIS protein content was found for pregnant mice, whereas the abundance of the other SOCS proteins analyzed and SH2-Bbeta did not significantly change compared with virgin animals. The desensitization of the JAK2/STAT5b GH signaling pathway observed in pregnant mice would then be mainly related to increased CIS levels rather than to the other regulatory proteins examined.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas, University of Buenos Aires-Consejo Nacional de Investigaciones Cientificar y Techicas (CONICET), Buenos Aires, Argentina.
authors.forename: Johanna G
authors.initials: JG
authors.lastname: Miquet
authors.forename: Ana I
authors.initials: AI
authors.lastname: Sotelo
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
authors.forename: Daniel
authors.initials: D
authors.lastname: Turyn
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D013006:Growth Hormone / Q000378:metabolism / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D053614:Janus Kinase 2; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008894:Milk Proteins / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D013006:Growth Hormone; D017874:Immediate-Early Proteins; D053614:Janus Kinase 2; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; C494096:Stat5b protein, mouse; C507926:Jak2 protein, mouse