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Gene Review

Cish  -  cytokine inducible SH2-containing protein

Mus musculus

Synonyms: AI385595, CIS, CIS-1, CIS1, Cis, ...


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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


Biological context of Cish


Anatomical context of Cish


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


Regulatory relationships of Cish


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


  1. Growth hormone down-regulation of Interleukin-1beta and Interleukin-6 induced acute phase protein gene expression is associated with increased gene expression of suppressor of cytokine signal-3. Wu, X., Herndon, D.N., Wolf, S.E. Shock (2003) [Pubmed]
  2. Leptin treatment increases suppressors of cytokine signaling in central and peripheral tissues. Emilsson, V., Arch, J.R., de Groot, R.P., Lister, C.A., Cawthorne, M.A. FEBS Lett. (1999) [Pubmed]
  3. Suppressors of cytokine signalling and regulation of growth hormone action. Greenhalgh, C.J., Alexander, W.S. Growth Horm. IGF Res. (2004) [Pubmed]
  4. Suppressors of cytokine signaling: Relevance to gastrointestinal function and disease. Greenhalgh, C.J., Miller, M.E., Hilton, D.J., Lund, P.K. Gastroenterology (2002) [Pubmed]
  5. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Ueki, K., Kondo, T., Kahn, C.R. Mol. Cell. Biol. (2004) [Pubmed]
  6. Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. Palmer, D.C., Guittard, G.C., Franco, Z., Crompton, J.G., Eil, R.L., Patel, S.J., Ji, Y., Van Panhuys, N., Klebanoff, C.A., Sukumar, M., Clever, D., Chichura, A., Roychoudhuri, R., Varma, R., Wang, E., Gattinoni, L., Marincola, F.M., Balagopalan, L., Samelson, L.E., Restifo, N.P. J. Exp. Med. (2015) [Pubmed]
  7. Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Lin, S.P., Youngson, N., Takada, S., Seitz, H., Reik, W., Paulsen, M., Cavaille, J., Ferguson-Smith, A.C. Nat. Genet. (2003) [Pubmed]
  8. A family of cytokine-inducible inhibitors of signalling. Starr, R., Willson, T.A., Viney, E.M., Murray, L.J., Rayner, J.R., Jenkins, B.J., Gonda, T.J., Alexander, W.S., Metcalf, D., Nicola, N.A., Hilton, D.J. Nature (1997) [Pubmed]
  9. Modulation of c-fos gene transcription by negative and positive cellular factors. Sassone-Corsi, P., Verma, I.M. Nature (1987) [Pubmed]
  10. Cis association of Ly49A with MHC class I restricts natural killer cell inhibition. Doucey, M.A., Scarpellino, L., Zimmer, J., Guillaume, P., Luescher, I.F., Bron, C., Held, W. Nat. Immunol. (2004) [Pubmed]
  11. Estrogen up-regulates hepatic expression of suppressors of cytokine signaling-2 and -3 in vivo and in vitro. Leong, G.M., Moverare, S., Brce, J., Doyle, N., Sjögren, K., Dahlman-Wright, K., Gustafsson, J.A., Ho, K.K., Ohlsson, C., Leung, K.C. Endocrinology (2004) [Pubmed]
  12. Mycobacterium bovis bacillus Calmette-Guérin infection promotes SOCS induction and inhibits IFN-gamma-stimulated JAK/STAT signaling in J774 macrophages. Imai, K., Kurita-Ochiai, T., Ochiai, K. FEMS Immunol. Med. Microbiol. (2003) [Pubmed]
  13. Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. Ebert, B.L., Firth, J.D., Ratcliffe, P.J. J. Biol. Chem. (1995) [Pubmed]
  14. Combination chemotherapy with a new folate analog: activity of 10-ethyl-10-deaza-aminopterin compared to methotrexate with 5-fluorouracil and alkylating agents against advanced metastatic disease in murine tumor models. Schmid, F.A., Sirotnak, F.M., Otter, G.M., DeGraw, J.I. Cancer treatment reports. (1987) [Pubmed]
  15. Regulation and function of the cytokine-inducible SH-2 domain proteins, CIS and SOCS3, in mammary epithelial cells. Tonko-Geymayer, S., Goupille, O., Tonko, M., Soratroi, C., Yoshimura, A., Streuli, C., Ziemiecki, A., Kofler, R., Doppler, W. Mol. Endocrinol. (2002) [Pubmed]
  16. Cytokine-inducible SH2 protein up-regulation is associated with desensitization of GH signaling in GHRH-transgenic mice. González, L., Miquet, J.G., Sotelo, A.I., Bartke, A., Turyn, D. Endocrinology (2002) [Pubmed]
  17. Cytokine-inducible SH2 protein (CIS3) and JAK2 binding protein (JAB) abolish prolactin receptor-mediated STAT5 signaling. Helman, D., Sandowski, Y., Cohen, Y., Matsumoto, A., Yoshimura, A., Merchav, S., Gertler, A. FEBS Lett. (1998) [Pubmed]
  18. Differential roles of SOCS family members in EpoR signal transduction. Jegalian, A.G., Wu, H. J. Interferon Cytokine Res. (2002) [Pubmed]
  19. Modulation of the activation status of Stat5a during LIF-induced differentiation of M1 myeloid leukemia cells. Piekorz, R.P., Rinke, R., Gouilleux, F., Neumann, B., Groner, B., Hocke, G.M. Biochim. Biophys. Acta (1998) [Pubmed]
  20. PRL receptor-mediated effects in female mouse adipocytes: PRL induces suppressors of cytokine signaling expression and suppresses insulin-induced leptin production in adipocytes in vitro. Ling, C., Billig, H. Endocrinology (2001) [Pubmed]
  21. Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Matsumoto, A., Seki, Y., Kubo, M., Ohtsuka, S., Suzuki, A., Hayashi, I., Tsuji, K., Nakahata, T., Okabe, M., Yamada, S., Yoshimura, A. Mol. Cell. Biol. (1999) [Pubmed]
  22. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. Yoshimura, A., Ohkubo, T., Kiguchi, T., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Hara, T., Miyajima, A. EMBO J. (1995) [Pubmed]
  23. CIS1 interacts with the Y532 of the prolactin receptor and suppresses prolactin-dependent STAT5 activation. Endo, T., Sasaki, A., Minoguchi, M., Joo, A., Yoshimura, A. J. Biochem. (2003) [Pubmed]
  24. Functional association of cytokine-induced SH2 protein and protein kinase C in activated T cells. Chen, S., Anderson, P.O., Li, L., Sjögren, H.O., Wang, P., Li, S.L. Int. Immunol. (2003) [Pubmed]
  25. SOCS up-regulation mobilizes autologous stem cells through CXCR4 blockade. Pello, O.M., Del Carmen Moreno-Ortiz, M., Rodr??guez-Frade, J.M., Mart??nez-Mu??oz, L., Lucas, D., G??mez, L., Lucas, P., Samper, E., Aracil, M., Mart??nez-A, C., Bernad, A., Mellado, M. Blood (2006) [Pubmed]
  26. Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. Dalpke, A.H., Opper, S., Zimmermann, S., Heeg, K. J. Immunol. (2001) [Pubmed]
  27. Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3. Denson, L.A., Held, M.A., Menon, R.K., Frank, S.J., Parlow, A.F., Arnold, D.L. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  28. Cis- and trans-acting elements required for constitutive and cytokine-regulated expression of the mouse complement C3 gene. Kawamura, N., Singer, L., Wetsel, R.A., Colten, H.R. Biochem. J. (1992) [Pubmed]
  29. Cytokine-induced Src homology 2 protein (CIS) promotes T cell receptor-mediated proliferation and prolongs survival of activated T cells. Li, S., Chen, S., Xu, X., Sundstedt, A., Paulsson, K.M., Anderson, P., Karlsson, S., Sjögren, H.O., Wang, P. J. Exp. Med. (2000) [Pubmed]
  30. Desensitization of the JAK2/STAT5 GH signaling pathway associated with increased CIS protein content in liver of pregnant mice. Miquet, J.G., Sotelo, A.I., Bartke, A., Turyn, D. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  31. STAT5b mediates the GH-induced expression of SOCS-2 and SOCS-3 mRNA in the liver. Davey, H.W., McLachlan, M.J., Wilkins, R.J., Hilton, D.J., Adams, T.E. Mol. Cell. Endocrinol. (1999) [Pubmed]
  32. Expression of suppressors of cytokine signaling during liver regeneration. Campbell, J.S., Prichard, L., Schaper, F., Schmitz, J., Stephenson-Famy, A., Rosenfeld, M.E., Argast, G.M., Heinrich, P.C., Fausto, N. J. Clin. Invest. (2001) [Pubmed]
  33. The cytokine-inducible Scr homology domain-containing protein negatively regulates signaling by promoting apoptosis in erythroid progenitor cells. Ketteler, R., Moghraby, C.S., Hsiao, J.G., Sandra, O., Lodish, H.F., Klingmüller, U. J. Biol. Chem. (2003) [Pubmed]
  34. Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Jo, D., Liu, D., Yao, S., Collins, R.D., Hawiger, J. Nat. Med. (2005) [Pubmed]
  35. Chromatin acetylation and remodeling at the Cis promoter during STAT5-induced transcription. Rascle, A., Lees, E. Nucleic Acids Res. (2003) [Pubmed]
  36. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. Adams, T.E., Hansen, J.A., Starr, R., Nicola, N.A., Hilton, D.J., Billestrup, N. J. Biol. Chem. (1998) [Pubmed]
  37. Activation of STAT signaling pathways and induction of suppressors of cytokine signaling (SOCS) proteins in mammalian lens by growth factors. Ebong, S., Yu, C.R., Carper, D.A., Chepelinsky, A.B., Egwuagu, C.E. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
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