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This article is about the CISH gene. For other uses, see chromogenic in situ hybridization.
Cytokine inducible SH2-containing protein
Symbols CISH ; BACTS2; CIS; CIS-1; G18; SOCS
External IDs OMIM602441 MGI103159 HomoloGene7667 GeneCards: CISH Gene
RNA expression pattern
PBB GE CISH 221223 x at tn.png
More reference expression data
Species Human Mouse
Entrez 1154 12700
Ensembl ENSG00000114737 ENSMUSG00000032578
UniProt Q9NSE2 Q62225
RefSeq (mRNA) NM_013324 NM_009895
RefSeq (protein) NP_037456 NP_034025
Location (UCSC) Chr 3:
50.64 – 50.65 Mb
Chr 9:
107.3 – 107.3 Mb
PubMed search [1] [2]

Cytokine-inducible SH2-containing protein is a protein that in humans is encoded by the CISH gene.[1][2][3] CISH orthologs [4] have been identified in most mammals with sequenced genomes. CISH controls interleukin-2 signaling, and variations of CISH with certain SNPs are associated with susceptibility to bacteremia, tuberculosis and malaria.[5]

The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor.[3]

Model organisms[edit]

Model organisms have been used in the study of CISH function. A conditional knockout mouse line, called Cishtm1a(KOMP)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[12][13][14]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed.[8]


CISH has been shown to interact with IL2RB[16] and Growth hormone receptor.[17]


  1. ^ Uchida K, Yoshimura A, Inazawa J, Yanagisawa K, Osada H, Masuda A, Saito T, Takahashi T, Miyajima A, Takahashi T (Mar 1998). "Molecular cloning of CISH, chromosome assignment to 3p21.3, and analysis of expression in fetal and adult tissues". Cytogenet Cell Genet 78 (3–4): 209–12. doi:10.1159/000134658. PMID 9465889. 
  2. ^ Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A (Aug 1995). "A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors". EMBO J 14 (12): 2816–26. PMC 398400. PMID 7796808. 
  3. ^ a b "Entrez Gene: CISH cytokine inducible SH2-containing protein". 
  4. ^ "OrthoMaM phylogenetic marker: CISH coding sequence". 
  5. ^ Khor CC; Vannberg FO; Chapman SJ et al. (June 2010). "CISH and susceptibility to infectious diseases". N. Engl. J. Med. 362 (22): 2092–101. doi:10.1056/NEJMoa0905606. PMID 20484391.  [Free Text]
  6. ^ "Salmonella infection data for Cish". Wellcome Trust Sanger Institute. 
  7. ^ "Citrobacter infection data for Cish". Wellcome Trust Sanger Institute. 
  8. ^ a b c Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x. 
  9. ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  10. ^ "International Knockout Mouse Consortium". 
  11. ^ "Mouse Genome Informatics". 
  12. ^ Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.  edit
  13. ^ Dolgin E (June 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718. 
  14. ^ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  15. ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353. 
  16. ^ Aman, M J; Migone T S; Sasaki A; Ascherman D P; Zhu M h; Soldaini E; Imada K; Miyajima A; Yoshimura A; Leonard W J (Oct 1999). "CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling". J. Biol. Chem. (UNITED STATES) 274 (42): 30266–72. doi:10.1074/jbc.274.42.30266. ISSN 0021-9258. PMID 10514520. 
  17. ^ Ram, P A; Waxman D J (Dec 1999). "SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms". J. Biol. Chem. (UNITED STATES) 274 (50): 35553–61. doi:10.1074/jbc.274.50.35553. ISSN 0021-9258. PMID 10585430. 

Further reading[edit]

  • Kile BT; Schulman BA; Alexander WS et al. (2002). "The SOCS box: a tale of destruction and degradation". Trends Biochem. Sci. 27 (5): 235–41. doi:10.1016/S0968-0004(02)02085-6. PMID 12076535. 
  • Verdier F; Chrétien S; Muller O et al. (1998). "Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation. Possible involvement of the ubiquitinated Cis protein". J. Biol. Chem. 273 (43): 28185–90. doi:10.1074/jbc.273.43.28185. PMID 9774439. 
  • Aman MJ; Migone TS; Sasaki A et al. (1999). "CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling". J. Biol. Chem. 274 (42): 30266–72. doi:10.1074/jbc.274.42.30266. PMID 10514520. 
  • Okabe S; Tauchi T; Morita H et al. (1999). "Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway". Exp. Hematol. 27 (10): 1542–7. doi:10.1016/S0301-472X(99)00094-6. PMID 10517496. 
  • Jiang C; Yu L; Zhao Y et al. (2000). "Cloning and characterization of CIS 1b (cytokine inducible SH2-containing protein 1b), an alternative splicing form of CIS 1 gene". DNA Seq. 11 (1–2): 149–54. doi:10.3109/10425170009033983. PMID 10902923. 
  • Dogusan Z; Hooghe-Peters EL; Berus D et al. (2000). "Expression of SOCS genes in normal and leukemic human leukocytes stimulated by prolactin, growth hormone and cytokines". J. Neuroimmunol. 109 (1): 34–9. doi:10.1016/S0165-5728(00)00300-3. PMID 10969179. 
  • Yousefi S; Cooper PR; Mueck B et al. (2000). "cDNA representational difference analysis of human neutrophils stimulated by GM-CSF". Biochem. Biophys. Res. Commun. 277 (2): 401–9. doi:10.1006/bbrc.2000.3678. PMID 11032736. 
  • Dif F; Saunier E; Demeneix B et al. (2001). "Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor". Endocrinology 142 (12): 5286–93. doi:10.1210/endo.142.12.8549. PMID 11713228. 
  • Federici M; Giustizieri ML; Scarponi C et al. (2002). "Impaired IFN-gamma-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1". J. Immunol. 169 (1): 434–42. doi:10.4049/jimmunol.169.1.434. PMID 12077274. 
  • Strausberg RL; Feingold EA; Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. 
  • Du L; Frick GP; Tai LR et al. (2003). "Interaction of the growth hormone receptor with cytokine-induced Src homology domain 2 protein in rat adipocytes". Endocrinology 144 (3): 868–76. doi:10.1210/en.2002-220830. PMID 12586763. 
  • Chen S; Anderson PO; Li L et al. (2003). "Functional association of cytokine-induced SH2 protein and protein kinase C in activated T cells". Int. Immunol. 15 (3): 403–9. doi:10.1093/intimm/dxg039. PMID 12618484. 
  • Yamasaki K; Hanakawa Y; Tokumaru S et al. (2003). "Suppressor of cytokine signaling 1/JAB and suppressor of cytokine signaling 3/cytokine-inducible SH2 containing protein 3 negatively regulate the signal transducers and activators of transcription signaling pathway in normal human epidermal keratinocytes". J. Invest. Dermatol. 120 (4): 571–80. doi:10.1046/j.1523-1747.2003.12100.x. PMID 12648219. 
  • Cheng J, Zhang D, Zhou C, Marasco WA (2004). "Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells". Leuk. Res. 28 (1): 71–82. doi:10.1016/S0145-2126(03)00158-9. PMID 14630083. 
  • Bayle J; Letard S; Frank R et al. (2004). "Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling". J. Biol. Chem. 279 (13): 12249–59. doi:10.1074/jbc.M313381200. PMID 14707129. 
  • Colland F; Jacq X; Trouplin V et al. (2004). "Functional Proteomics Mapping of a Human Signaling Pathway". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748. 
  • Hunter MG; Jacob A; O'donnell LC et al. (2004). "Loss of SHIP and CIS recruitment to the granulocyte colony-stimulating factor receptor contribute to hyperproliferative responses in severe congenital neutropenia/acute myelogenous leukemia". J. Immunol. 173 (8): 5036–45. doi:10.4049/jimmunol.173.8.5036. PMID 15470047.