Lack of Socs2 Expression Causes the High-Growth Phenotype in Mice (original) (raw)
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Journal of Endocrinology, 2010
Circulating signalling proteins have often been divided into hormones and cytokines, but it is increasingly being recognised that these substances have a number of common characteristics and mechanisms of action. This is clearly illustrated by the suppressor of cytokine signalling (SOCS) proteins which are increasingly seen as a central component of the regulation of the action of hormones and cytokines that signal through the cytokine receptor complex. The SOCS protein family is probably more extensive than currently recognised; its members may have differential tissue expression and their potency for suppressing cytokine signalling may vary. Recent knockout and transgenic studies in mice have highlighted the role that these proteins play in growth and skeletal development as well as in inflammation. Chronic inflammation is associated with altered growth and skeletal development, and it is possible that SOCS proteins may have an important role to play in mediating these effects.
SOCS2 regulation of growth hormone signaling requires a canonical interaction with phosphotyrosine
Suppressor Of Cytokine Signaling (SOCS) 2 is the critical negative regulator of growth hormone (GH) and prolactin signaling. Mice lacking SOCS2 display gigantism with increased body weight and length, and an enhanced response to GH treatment. Here we characterized mice carrying a germ-line R96C mutation within the SOCS2-SH2 domain, which disrupts the ability of SOCS2 to interact with tyrosine phosphorylated targets. Socs2R96C/R96C mice displayed a similar increase in growth as previously observed in SOCS2 null (Socs2-/-) mice, with a proportional increase in body and organ weight, and bone length. Embryonic fibroblasts isolated from Socs2R96C/R96C and Socs2-/- mice also showed a comparable increase in phosphorylation of STAT5 following GH stimulation, indicating the critical role of phosphotyrosine binding in SOCS2 function.
SOCS2 negatively regulates growth hormone action in vitro and in vivo
Journal of Clinical Investigation, 2005
Mice deficient in SOCS2 display an excessive growth phenotype characterized by a 30-50% increase in mature body size. Here we show that the SOCS2 -/phenotype is dependent upon the presence of endogenous growth hormone (GH) and that treatment with exogenous GH induced excessive growth in mice lacking both endogenous GH and SOCS2. This was reflected in terms of overall body weight, body and bone lengths, and the weight of internal organs and tissues. A heightened response to GH was also measured by examining GH-responsive genes expressed in the liver after exogenous GH administration. To further understand the link between SOCS2 and the GH-signaling cascade, we investigated the nature of these interactions using structure/function and biochemical interaction studies. Analysis of the 3 structural motifs of the SOCS2 molecule revealed that each plays a crucial role in SOCS2 function, with the conserved SOCS-box motif being essential for all inhibitory function. SOCS2 was found to bind 2 phosphorylated tyrosines on the GH receptor, and mutational analysis of these amino acids showed that both were essential for SOCS2 function. Together, the data provide clear evidence that SOCS2 is a negative regulator of GH signaling.
Molecular Endocrinology, 2005
Suppressor of cytokine signaling-2 (SOCS2)-deficient (SOCS2 ؊/؊) mice grow significantly larger than their littermates, suggesting that SOCS2 is important in the negative regulation of the actions of GH and/or IGF-I. The aim of this study was to identify genes and metabolic parameters that might contribute to the SOCS2 ؊/؊ phenotype. We demonstrate that although SOCS2 deficiency induces significant changes in hepatic gene expression, only a fraction of these overlap with known GH-induced effects in the liver, suggesting that SOCS2 might be an important regulator of other growth factors and cytokines acting on the liver. However, an important role of GH and IGF-I in the phenotype of these animals was demonstrated by an overexpression of IGF-binding protein-3 mRNA in the liver and increased levels of circulating IGFbinding protein-3. Other GH-like effects included
Molecular Endocrinology, 2002
Mice lacking suppressor of cytokine signaling-2 (SOCS-2) exhibit accelerated postnatal growth resulting in adult mice that are 1.3 to 1.5 times the size of normal mice. In this study we examined the somatotrophic pathway to determine whether the production or actions of GH or IGF-I are altered in these mice. We demonstrated that SOCS-2 ؊/؊ mice do not have elevated GH levels and suffer no major pituitary dysmorphogenesis, and that SOCS-2-deficient embryonic fibroblasts do not have al-tered IGF-I signaling. Primary hepatocytes from SOCS-2 ؊/؊ mice, however, did have moderately prolonged signal transducer and activator of transcription 5 signaling in response to GH stimulation. Furthermore, the deletion of SOCS-2 from mice also lacking signal transducer and activator of transcription 5b had little effect on growth, suggesting that the action of SOCS-2 may be the regulation of the GH signaling pathway. (Molecular
Journal of Pediatric Endocrinology and Metabolism, 2012
Background/aim: Possible etiologies of idiopathic short stature (ISS) include a range of conditions, some of which may be caused by defects in the modulation of the growth hormone (GH)-signaling pathway. The Janus kinase/ signal transducer and activator of transcription pathway is regulated by several mechanisms, including negative feedback regulation by the suppressors of cytokine signaling (SOCS). However, the specifi c induction of SOCS transcript levels in fi broblasts from ISS patients has not been studied. Methods: We determined the transcript levels of the SOCS1-3 genes under basal conditions, and in the presence or absence of stimulation with rhGH for 24 h in skin fi broblast cultures obtained from patients with ISS and children with normal height. Results: Under basal conditions, ISS patients express higher SOCS2-3 transcript levels than control children. After incubation with recombinant human GH (rhGH), the transcript levels of SOCS2 increased signifi cantly in ISS patients compared to controls (0.79 ± 0.06 vs. 0.55 ± 0.07; p = 0.03), a pattern which did not achieve statistical signifi cance for SOCS3 transcript levels (0.55 ± 0.08 vs. 0.40 ± 0.07). Conclusion: The higher baseline transcript levels of the SOCS genes, and the increase observed for SOCS2 after rhGH treatment in ISS patients, suggest that growth retardation in some of these children may be mediated, at least in part, by intracellular overexpression of the SOCS genes.
Molecular and cellular biology, 2002
SOCS-6 is a member of the suppressor of cytokine signaling (SOCS) family of proteins (SOCS-1 to SOCS-7 and CIS) which each contain a central SH2 domain and a carboxyl-terminal SOCS box. SOCS-1, SOCS-2, SOCS-3, and CIS act to negatively regulate cytokine-induced signaling pathways; however, the actions of SOCS-4, SOCS-5, SOCS-6, and SOCS-7 remain less clear. Here we have used both biochemical and genetic approaches to examine the action of SOCS-6. We found that SOCS-6 and SOCS-7 are expressed ubiquitously in murine tissues. Like other SOCS family members, SOCS-6 binds to elongins B and C through its SOCS box, suggesting that it might act as an E3 ubiquitin ligase that targets proteins bound to its SH2 domain for ubiquitination and proteasomal degradation. We investigated the binding specificity of the SOCS-6 and SOCS-7 SH2 domains and found that they preferentially bound to phosphopeptides containing a valine in the phosphotyrosine (pY) +1 position and a hydrophobic residue in the pY...
Roles of Growth Hormone and Insulin-like Growth Factor 1 in Mouse Postnatal Growth
Developmental Biology, 2001
To examine the relationship between growth hormone (GH) and insulin-like growth factor 1 (IGF1) in controlling postnatal growth, we performed a comparative analysis of dwarfing phenotypes manifested in mouse mutants lacking GH receptor, IGF1, or both. This genetic study has provided conclusive evidence demonstrating that GH and IGF1 promote postnatal growth by both independent and common functions, as the growth retardation of double Ghr/Igf1 nullizygotes is more severe than that observed with either class of single mutant. In fact, the body weight of these double-mutant mice is only ϳ17% of normal and, in absolute magnitude (ϳ5 g), only twice that of the smallest known mammal. Thus, the growth control pathway in which the components of the GH/IGF1 signaling systems participate constitutes the major determinant of body size. To complement this conclusion mainly based on extensive growth curve analyses, we also present details concerning the involvement of the GH/IGF1 axis in linear growth derived by a developmental study of long bone ossification in the mutants.