Disease relevance of Cish

• In this study, we hypothesized that the inhibitory effect of GH on the hepatic acute phase response was due to increased suppressor of cytokine signaling (SOCS) gene expression [1].
• Forced expression of CIS in insulinoma cells prevented transactivation mediated by leptin [2].
• A precise understanding of the actions of SOCS proteins in GH signalling may offer new opportunities for therapeutic intervention in growth disorders and other conditions involving GH action [3].
• CONCLUSIONS: Information about SOCS action in gastrointestinal function and disease is only just emerging, but available data indicate a role in growth of gastrointestinal tissues, inflammatory bowel disease, and cancer [4].
• Here we show that in both obesity and lipopolysaccharide (LPS)-induced endotoxemia there is an increase in suppressor of cytokine signaling (SOCS) proteins, SOCS-1 and SOCS-3, in liver, muscle, and, to a lesser extent, fat [5].
• CISH is induced by T cell receptor (TCR) ligation and negatively regulates it by targeting the critical signaling intermediate PLC-gamma-1 for degradation [6]. The deletion of Cish in effector T cells has been shown to augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. There are no changes in activity or phosphorylation of Cish's purported target STAT5 in either the presence or absence of Cish.

High impact information on Cish

• Cis-acting regulatory elements that control imprinting are not fully understood but involve regions that become differentially methylated on the two parental chromosomes during male and female gametogenesis [7].
• Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction [8].
• Cis-acting DNA sequences, frequently located upstream of the TATA box, have been implicated in modulating the expression of many genes [9].
• Cis association and trans interaction occur through the same binding site [10].
• Cis association of Ly49A with MHC class I restricts natural killer cell inhibition [10].

Chemical compound and disease context of Cish

• In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR [11].
• Mycobacterium bovis bacillus Calmette-Guérin infection promotes SOCS induction and inhibits IFN-gamma-stimulated JAK/STAT signaling in J774 macrophages [12].
• We also observed that trehalose 6,6'-dimycolate/cord factor, a major component of the Mycobacterium tuberculosis cell wall, induces expression of SOCS and inhibits IFN-gamma-stimulated phosphorylation of STAT1 extensively in the cells [12].
• Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences [13].
• Against the L1210 leukemia, 10EDAM was the most active agent followed in descending order by MTX, CPA, 5-FU, L-PAM, and Cis Pt [14].

Biological context of Cish

• At the beginning of the lactation period both CIS and SOCS3 were high [15].
• Cytokine-inducible SH2 protein up-regulation is associated with desensitization of GH signaling in GHRH-transgenic mice [16].
• CIS1 expression in postpartum mouse mammary glands was high and changed little in the course of 3 days [17].
• Differential roles of SOCS family members in EpoR signal transduction [18].
• Similarly, high expression of the immediate early gene CIS (cytokine-inducible SH2-containing protein), a known target gene of Stat5 in hematopoietic cells, occurred only during the onset of differentiation [19].

Anatomical context of Cish

• We have studied the expression and function of CIS and SOCS3 proteins in the mouse mammary gland and in HC11 mammary epithelial cells [15].
• Regulation and function of the cytokine-inducible SH-2 domain proteins, CIS and SOCS3, in mammary epithelial cells [15].
• Furthermore, CIS, SOCS-3, and SOCS-2 mRNA and protein were all transiently expressed in adipose tissue obtained from female mice stimulated with oPRL (1 microg/g BW) for 0-24 h [20].
• In order to understand the effects of SOCS on EPO-mediated effects, we generated multiple stable cell lines that inducibly express particular SOCS proteins [18].
• These data suggest that CIS1 functions as a specific negative regulator of STAT5 in vivo and plays an important regulatory role in the liver, mammary glands, and T cells [21].

Associations of Cish with chemical compounds

• Forced expression of CIS by steroid reduced the growth rate of these transformants, suggesting a negative role of CIS in signal transduction [22].
• We expressed CIS1 fused to the DNA-binding domain and PRL receptor cytoplasmic domain fused to the transcription activation domain in the presence or absence of the tyrosine kinase domain of JAK2 in yeast [23].
• In addition to the interaction and intracellular co-localization of the CIS and PKC, an increase in the activation of AP-1 and NF-kappaB was noted in CIS-expressing T cells, after stimulation by either anti-CD3/CD28 or phorbol myristate acetate + ionomycin [24].
• Furthermore, in lethally irradiated mice reconstituted with bone marrow infected by a tetracycline-regulated, SOCS-expressing lentiviral vector, doxycycline treatment promoted rapid, extensive precursor mobilization to the periphery [25].
• SOCS mRNA expression could be blocked by chloroquine and was independent of protein synthesis [26].

Physical interactions of Cish

• Moreover, we determined that the phosphorylated Y532 of the murine PRL receptor is the binding site for CIS1 [23].

Regulatory relationships of Cish

• IL-6 inhibits hepatic GH signaling by upregulating Cis and Socs-3, which may involve activation of STAT3 [27].
• Ectopic expression of both SOCS3 and CIS inhibited STAT5 activation [15].
• In this study, we created CIS1 transgenic mice under the control of a beta-actin promoter [21].
• Cis- and trans-acting elements required for constitutive and cytokine-regulated expression of the mouse complement C3 gene [28].
• In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo [29].

Other interactions of Cish

• 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 [30].
• In contrast, the absence of STAT5b has no effect on the GH-induced expression of CIS and SOCS-2 mRNA in the mammary gland [31].
• SOCS-2 and CIS mRNA are only weakly induced, and SOCS-1 is not detectable [32].
• To facilitate the study of the interactions between CIS1 and the PRL receptor, we have developed the yeast tri-hybrid system, a modification of the yeast two-hybrid system [23].
• Accordingly, the retroviral expression of GFP-CIS but not GFP-CIS R107K impaired proliferation of erythroid progenitor cells in colony assays [33].

Analytical, diagnostic and therapeutic context of Cish

• Suppressor of cytokine signaling (SOCS) 3 attenuates proinflammatory signaling mediated by the signal transducer and activator of transcription (STAT) family of proteins [34].
• Using chromatin immunoprecipitation and accessibility assays, we characterized histone acetylation and chromatin remodeling events occurring during transcriptional activation of the endogenous murine Cis gene, a STAT5 target gene, in response to IL-3 [35].
• To address whether any of these genes are induced in response to growth hormone (GH), serum-starved 3T3-F442A fibroblasts were incubated with GH for various time points, and the expression of the SOCS gene family was analyzed by Northern blotting [36].
• CpG-DNA triggered synthesis of SOCS proteins that could be detected by Western blotting [26].
• METHODS: STAT activation and SOCS expression were analyzed in transgenic or wild-type mouse lens and lens epithelial cells stimulated with growth factors by immunohistochemistry, RT-PCR, Northern, Western, proliferation, or transient reporter assays [37].

References