SOCS (suppressor of cytokine signaling) proteins, also known as SSI (STAT-induced STAT inhibitor) proteins, have been shown to be negative regulators of cytokine receptor signaling via the Janus kinase signal transducer and activation of transcription (STAT; see OMIM 600555) pathway (the JAK/STAT pathway).
NCBI Summary:
This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma. The protein encoded by this gene can bind to JAK2 kinase, and inhibit the activity of JAK2 kinase. Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development. [provided by RefSeq, Jul 2008]
General function
Comment
Cellular localization
Cytoplasmic
Comment
Association of serum and follicular fluid leptin concentrations with granulosa cell phosphorylated signal transducer and activator of transcription 3 expression in fertile patients with polycystic ovarian syndrome. Li MG et al. (2007) Our objective was to evaluate whether polycystic ovarian syndrome (PCOS)-associated infertility is related to alterations of leptin, leptin receptor (Ob-R), and the phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/suppressor of cytokine signal 3 (SOCS3) system in the ovary. A case-control study was conducted in a university hospital. Thirty-one infertile PCOS women with oligoovulation plus polycystic ovarian morphology and 79 infertile women with tubal blockage (control) participated in the study. The subjects were stratified according to in vitro fertilization outcomes: successful and failed subgroups. Serum and follicular fluid (FF) leptin levels were measured with ELISA. RT-PCR and Western blotting were performed to assess expression of mRNA encoding leptin and Ob-R and proteins of p-STAT3 and SOCS3 in granulosa cells (GCs). Leptin levels in serum and FF of PCOS women were significantly higher than those of control (P < 0.01). There were no significant differences in expression of leptin mRNA and short and long Ob-Rs between PCOS and control (P > 0.05). The p-STAT3 level was decreased in PCOS compared with control (P < 0.01), whereas SOCS3 remained significantly unchanged (P > 0.05). Further analysis showed that serum and FF leptin levels were significantly higher, whereas p-STAT3 in GCs was lower in the failed subgroup of PCOS than those in the successful subgroup of PCOS (P < 0.05). Hyperleptinemia and high FF leptin are important pathologies of PCOS with infertility. Lower levels of p-STAT3 in GCs may be related to ovarian leptin resistance and fecundity in PCOS women. Relatively high serum and FF leptin and low p-STAT3 in GCs may account for decreased fertilization, implantation, and pregnancy rates of in vitro fertilization in PCOS women.//////////////////
Ovarian function
Luteolysis, Oocyte maturation
Comment
J. D. Curlewis, et al reported that a Prostaglandin F2 Analog Induces Suppressors of Cytokine Signaling-3 Expression in the Corpus Luteum of the Pregnant Rat.
PRL and placental lactogen (PL) play key roles in maintaining the rodent corpus luteum through pregnancy. Suppressors of cytokine signaling (SOCS) have been shown to decrease cell sensitivity to cytokines, including PRL, and the authors have addressed the issue of whether luteolysis induced by prostaglandin F2 (PGF2 ) might up-regulate SOCS proteins to inhibit PRL signaling. In d 19 pregnant rats, cloprostenol, a PGF2 analog, rapidly induced transcripts for SOCS-3 and, to a lesser extent, SOCS-1. They also found increased SOCS-3 protein in the ovary by immunoblot and in the corpus luteum by immunohistochemistry. Increased SOCS-3 expression was preceded by an increase in STAT3 tyrosine phosphorylation 10 min after cloprostenol injection and was maintained for 4 h, as determined by gel shift and immunohistochemistry. Induction of SOCS-3 was accompanied by a sharp decrease in active STAT5, as determined by gel-shift assay and by loss of nuclear localized STAT5. Four hours after cloprostenol administration, the corpus luteum was refractory to stimulation of STAT5 by PRL administration, and this was not due to down-regulation of PRL receptor. Therefore, induction of SOCS-3 by PGF2 may be an important element in the initiation of luteolysis via rapid suppression of luteotropic support from PL.
Expression regulated by
Eicosanoids
Comment
Ovarian localization
Cumulus, Luteal cells
Comment
Differences in the transcriptional profiles of human cumulus cells isolated from MI and MII oocytes of patients with polycystic ovary syndrome (PCOS). Huang X et al. Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Abnormalities of endocrine and intra-ovarian paracrine interactions may change the microenvironment for oocyte development during the folliculogenesis process and reduced oocyte development competence in PCOS patients who are sufferring from anovulatory infertility and pregnancy loss. In this microenvironment, the cross talk between the oocyte and surrounding cumulus cells (CCs) is critical for obtaining oocyte competence. The aim of our study was to investigate gene expression profile of CCs from PCOS patients undergoing IVF cycles in terms of oocyte maturity by using human Genome U133 Plus 2.0 microarrays. A total of 59 genes were differentially expressed between the two CC categories. Most of these genes were identified to be involved in one or more of the following pathways: receptor interactions, calcium signaling, metabolism and biosynthesis, focal adhesion, melanogenesis, leukocyte transendothelial migration, Wnt signaling pathway, and Type II diabetes mellitus. According to the different expression levels in the microarray and their putative functions, six differentially expressed genes (LHCGR, ANGPTL1, TNIK, GRIN2A, SFRP4 and SOCS3) were selected and analyzed by quantitative RT-PCR. The qRT-PCR results were consistent with the microarray data. Moreover, the molecular signatures (LHCGR, TNIK and SOCS3) were associated with developmental potential from embryo to blastocyst stage and were proposed as biomarkers for embryo viability in PCOS patients. Our results may have important clinically useful by offering a new potential strategy for competent oocyte/embryo selection in PCOS patients.
Maximal expression of Suppressors of Cytokine Signalling (SOCS) in the rat ovary occurs in late pregnancy. Anderson S et al. Maintenance of the rodent corpus luteum during pregnancy requires prolactin-receptor (PRL-R) signal transduction via STAT5. At the end of pregnancy prostaglandin F2alpha (PGF2alpha) induces luteal regression through many mechanisms, including down-regulation of PRL-R signaling. We have previously shown that a PGF2alpha analog upregulates Suppressors of Cytokine Signaling (SOCS) proteins in the corpus luteum of Day 19 pregnant rats leading to reduced STAT5 signaling. Here we examined endogenous SOCS expression and STAT5 signaling in the rat ovary during normal pregnancy and luteolysis. The mRNA expression of SOCS1, SOCS2 and SOCS3 and related Cytokine-inducible SH2-containing protein (CIS) was low in early pregnancy (Day 7), but significantly increased at mid-pregnancy (Days 10 and 13) associated with increased endogenous tyrosine phosphorylation (TyrP) of STAT5. In support of the notion that these changes are due to increasing placental lactogen levels at this time, we found that treatment with exogenous prolactin on Day 7 increased TyrP of STAT5 and induced SOCS mRNA expression, except SOCS3. After mid-pregnancy, further significant increases in SOCS3 and CIS mRNA expression were observed. Such changes in mRNA expression correlated with protein levels, with protein levels of both SOCS3 and CIS being maximal in late pregnancy (Days 19 to 21). In addition a significant reduction in TyrP of STAT5 was first observed on Day 20, with a further substantial decrease on Day 21. Therefore these results are consistent with the hypothesis that increased SOCS expression in the rat ovary during late pregnancy reduces STAT5 signaling which may be important in PGF2alpha-induced luteolysis.