Disease relevance of Socs2

• Socs2 induction seems B cell-specific, because no induction was observed in TCDD-responsive mouse hepatoma cells or human breast cancer cells [1].
• In particular, mice lacking SOCS2 display gigantism accompanied by evidence of deregulated GH signalling [2].
• In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P < 0.05) [3].
• Small variations in SOCS2 expression levels may significantly influence the outcome of therapeutic GH or acromegaly in intestine [4].
• Total body weight, daily weight gain, feed consumption and gain/feed, measured daily from 21 to 42 d of age, were all significantly greater (p less than .01) in the two lines with the hg/hg genotype (Ch and Gh) compared with their respective control lines (CH and GH) [5].

High impact information on Socs2

• These findings indicate that SOCS2 promotes neuronal differentiation by blocking growth hormone-mediated downregulation of Ngn1 [6].
• We found that expression of SOCS2, an intracellular regulator of cytokine signaling, was restricted to mouse progenitor cells and neurons in response to leukemia inhibitory factor (LIF)-like cytokines [6].
• 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 [7].
• Mice deficient in SOCS2 display an excessive growth phenotype characterized by a 30-50% increase in mature body size [7].
• This story began several years ago with the dramatic demonstration of gigantism in the SOCS2-knockout mouse [8].

Biological context of Socs2

• Promoter analysis revealed the presence of four dioxin-response elements within 1000 base pairs upstream of the Socs2 transcriptional start site, and a reporter gene regulated by the Socs2 promoter was inducible by TCDD [1].
• TCDD-mediated induction of Socs2 mRNA was dose-dependent and exhibited the characteristic structure-activity relationships observed for the aryl hydrocarbon receptor (AhR) ligands 3,3',4,4',5-pentachlorobiphenyl (PCB-126), indolo[3,2-b]-carbazole, and beta-naphthoflavone [1].
• Lack of Socs2 expression causes the high-growth phenotype in mice [9].
• We conclude that hg is an allele of the suppressor of cytokine signaling 2 (Socs2), a member of a family of regulators of cytokine signal transduction [9].
• By contrast, SOCS-2 and cytokine-inducible Src homology domain 2 (SH2)-containing protein up-regulate these processes [10].

Anatomical context of Socs2

• Experiments with cycloheximide and AhR-deficient B cells indicated that Socs2 mRNA induction is a primary effect that is AhR-dependent [1].
• We show here that CD4(+) naive T cells constitutively express low levels of SOCS1, SOCS2, and SOCS3 mRNAs [11].
• In contrast, the absence of STAT5b has no effect on the GH-induced expression of CIS and SOCS-2 mRNA in the mammary gland [12].
• Here we demonstrate that in 3T3-L1 adipocytes, insulin, a hormone whose receptor does not belong to the cytokine receptor family, induces SOCS-3 expression but not CIS or SOCS-2 [13].
• The level of SOCS-2 mRNA was also increased in adipose tissue during pregnancy and lactation compared with that in wild-type virgin female mice [14].

Associations of Socs2 with chemical compounds

• We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells [3].
• Interestingly, SOCS2-/- mice did not differ from their wild-type littermates in glucose or insulin tolerance tests, which is in contrast with the known diabetogenic effects of GH [15].

Physical interactions of Socs2

• GH-induced activation of STAT5 DNA binding activity was enhanced in intestine of SOCS2 null mice compared with WT control [4].

Other interactions of Socs2

• The Pre-SH2 domains of SOCS-2 and SOCS-3 confer the specificity of their regulatory function [10].
• Western blot analysis confirmed that Socs2 and Cyp1a1 protein levels were also induced in CH12.LX cells [1].
• In situ hybridisation analysis showed that SOCS-1 and SOCS-3 had a low and widespread pattern of expression, whereas SOCS-2 expression was higher and tightly regulated [16].
• In contrast, SOCS2 is less effective, and SOCS4 is ineffective at counteracting EPO-mediated events [17].
• We also report that growth hormone inhibited Ngn1 expression and neuronal production, and this action was blocked by SOCS2 overexpression [6].

Analytical, diagnostic and therapeutic context of Socs2

• Suppressor of cytokine signaling-2 (SOCS-2) is a member of the suppressor of cytokine signaling family, implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal transduction pathway [18].

References