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Gene Review

CISH  -  cytokine inducible SH2-containing protein

Homo sapiens

Synonyms: BACTS2, CIS, CIS-1, Cytokine-inducible SH2-containing protein, G18, ...
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Disease relevance of CISH


Psychiatry related information on CISH

  • In this study, the effect of MK-801 on various behaviours of bank voles, and in particular the relationship between CIS and PHIS, was investigated by repeated administration of MK-801 to stereotyping (ST) and non-stereotyping (NST) voles [5].
  • Significant predictors of good speech perception included greater nonverbal intelligence, smaller family size, longer use of the updated SPEAK/CIS processing strategy, a fully active electrode array, greater electrical dynamic range between threshold and maximum comfort level, and greater growth of loudness with increasing stimulus intensity [6].
  • METHODS: In employees with very low or very high fatigue levels, psychometrics of the Penn State Worry Questionnaire (PSWQ; measuring pathological worry) and the Checklist Individual Strength (CIS; measuring fatigue) were examined and their cross-sectional and longitudinal associations were explored [7].
  • Neurogenic erectile dysfunction was considered in the remaining 4 patients (4.4%) with a positive response to the CIS test, abnormal findings on NPT monitoring, and a normal vascular system with color Doppler ultrasound [8].
  • CASE STUDY: INTESTINAL OBSTRUCTION: Graduate Health Systems, a multisite integrated provider in the Philadelphia area, has used CADU/CIS to improve quality problems, reduce treatment-intensity variations, and improve clinical participation in care process evaluation and decision making [9].

High impact information on CISH

  • The CIS family of proteins (also referred to as the SOCS or SSI family) has been implicated in the regulation of signal transduction by a variety of cytokines [10].
  • These findings suggest mechanisms that regulate the assembly and activity of Cul5 E3 complexes through phosphorylation or autoubiquitination of the SOCS-box protein, and identify interactions between Vif and host cell proteins that may be therapeutic targets [11].
  • In this SOCS box, alanine replaces the consensus cysteine in the previously identified SOCS box [12].
  • This new motif was necessary but insufficient for interaction with Cul5-ElonginB-ElonginC, as two highly conserved Cys residues outside the SOCS box were required to interact with Cul5 but not ElonginC [12].
  • The suppressors of cytokine signaling (SOCS) and cytokine-inducible SH2 protein are key physiological regulators of the immune system [13].

Chemical compound and disease context of CISH

  • Aberrant methylation of these SOCS genes correlated with transcriptional silencing in ovarian and breast cancer cell lines, since expression was induced by the demethylating agent 5-azadeoxycytidine [14].
  • In order to elucidate the role of the membrane adenosine triphosphate binding cassette-transporter cMOAT (canalicular multispecific anion transporter) (MRP2/ABCC2) in cisplatin resistance of melanoma, the expression of this protein was analyzed in the platinum drug-resistant cell line MeWo CIS 1 [15].
  • To date, the majority of experience with the medical management of CIS of the bladder is with chemotherapeutic agent doxorubicin and the immunotherapeutic agent BCG [16].
  • A study on the in vitro sensitivity of tumour cells from patients with ovarian cancer has been carried out in parallel with a clinical study designed to evaluate the role of high-dose cis-platinum (CIS) as first-line chemotherapy [17].
  • The role of estrogen as a promoter agent of sporadic breast cancer has been considered by assaying, in benign breast disease (BBD) and in situ carcinomas (CIS), 2 markers, the estrogen receptor alpha (ERalpha) and cathepsin D (cath-D) involved in estrogen action on mammary tissue [18].

Biological context of CISH

  • Suppressors of cytokine signaling (SOCS) proteins are stimulated in response to cytokine-inducible STAT phosphorylation, acting in a negative-feedback mechanism to hinder cytokine receptor activity [19].
  • Comparison with cytokine-dependent BaF3 cells stimulated with interleukin-3 (IL-3) further reveals that CIS induction correlates with specific STAT5b post-translational modifications [1].
  • In the present study, a novel human cDNA (CIS1b) which proved to be a variant of CIS1 gene was isolated by screen human placenta lambda gt11 cDNA library and 5'-rapid amplification of cDNA ends (RACE) [20].
  • Furthermore, the gene structure of CIS1 was determined by comparing the cDNA sequences of CIS1 and CIS1b to the genomic sequence in human chromosome 3p21 [20].
  • Cloning and characterization of CIS 1b (cytokine inducible SH2-containing protein 1b), an alternative splicing form of CIS 1 gene [20].

Anatomical context of CISH


Associations of CISH with chemical compounds

  • Unlike CIS, SOCS-3 was rapidly tyrosine phosphorylated in response to IL-2 [25].
  • Although a functional SH2 binding domain of CIS was not required for its interaction with IL-2Rbeta in vitro, its phosphotyrosine binding capability was essential for the inhibitory action of CIS [26].
  • We have devised a protocol to generate probes for CISH that can be applied to formalin-fixed, paraffin-embedded tissue sections (FFPETS) [27].
  • 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 [28].
  • Vif binding to EloC is negatively regulated by serine phosphorylation in the BC-box motif of the SOCS-box [11].

Regulatory relationships of CISH


Other interactions of CISH

  • Inhibition of PRL hormone signaling by suppressor of cytokine signaling (SOCS)/cytokine-inducible SH2-containing protein (CIS) was investigated in transfected HEK 293 cells [29].
  • Characterization of STAT5B phosphorylation correlating with expression of cytokine-inducible SH2-containing protein (CIS) [1].
  • Several members, including CIS (cytokine-inducible SH2 protein), SOCS1 and SOCS3, are induced rapidly upon cytokine receptor activation and function in a negative-feedback loop, attenuating signalling at the receptor level [30].
  • CIS is also a well-known target gene of signal transducer and activator of transcription 5 (STAT5) pathways, providing normal negative feedback control of signaling by cytokines and growth factors [1].
  • Isolated RNA was subjected to semiquantitative reverse transcriptase polymerase chain reaction analysis of CIS/JAB expression [31].
  • A non-overlapping recruitment pattern is observed for SOCS2 and CIS with positions Y487 and Y595 as major binding sites, ruling out SOCS-mediated inhibition of STAT5 activation by competition for shared binding sites [32].

Analytical, diagnostic and therapeutic context of CISH


  1. Characterization of STAT5B phosphorylation correlating with expression of cytokine-inducible SH2-containing protein (CIS). Cooper, J.C., Boustead, J.N., Yu, C.L. Cell. Signal. (2006) [Pubmed]
  2. 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. Yamasaki, K., Hanakawa, Y., Tokumaru, S., Shirakata, Y., Sayama, K., Hanada, T., Yoshimura, A., Hashimoto, K. J. Invest. Dermatol. (2003) [Pubmed]
  3. Suppressor of cytokine signalling gene expression is elevated in breast carcinoma. Raccurt, M., Tam, S.P., Lau, P., Mertani, H.C., Lambert, A., Garcia-Caballero, T., Li, H., Brown, R.J., McGuckin, M.A., Morel, G., Waters, M.J. Br. J. Cancer (2003) [Pubmed]
  4. Nutritional regulation of leptin signaling. Ribiere, C., Plut, C. Current hypertension reports. (2005) [Pubmed]
  5. Dissociation between MK-801- and captivity-induced stereotypies in bank voles. Vandebroek, I., Berckmoes, V., Odberg, F.O. Psychopharmacology (Berl.) (1998) [Pubmed]
  6. Factors associated with development of speech perception skills in children implanted by age five. Geers, A., Brenner, C., Davidson, L. Ear and hearing. (2003) [Pubmed]
  7. The relation between pathological worrying and fatigue in a working population. Andrea, H., Beurskens, A.J., Kant, I., Davey, G.C., Field, A.P., van Schayck, C.P. Journal of psychosomatic research. (2004) [Pubmed]
  8. Honeymoon impotence: psychogenic or organic in origin? Usta, M.F., Erdoğru, T., Tefekli, A., Köksal, T., Yücel, B., Kadioğlu, A. Urology (2001) [Pubmed]
  9. Improving performance with clinical decision support. Brailer, D.J., Goldfarb, S., Horgan, M., Katz, F., Paulus, R.A., Zakrewski, K. The Joint Commission journal on quality improvement. (1996) [Pubmed]
  10. Negative regulation of cytokine signaling pathways. Yasukawa, H., Sasaki, A., Yoshimura, A. Annu. Rev. Immunol. (2000) [Pubmed]
  11. Phosphorylation of a novel SOCS-box regulates assembly of the HIV-1 Vif-Cul5 complex that promotes APOBEC3G degradation. Mehle, A., Goncalves, J., Santa-Marta, M., McPike, M., Gabuzda, D. Genes Dev. (2004) [Pubmed]
  12. Selective assembly of HIV-1 Vif-Cul5-ElonginB-ElonginC E3 ubiquitin ligase complex through a novel SOCS box and upstream cysteines. Yu, Y., Xiao, Z., Ehrlich, E.S., Yu, X., Yu, X.F. Genes Dev. (2004) [Pubmed]
  13. Suppressors of cytokine signaling and immunity. Kubo, M., Hanada, T., Yoshimura, A. Nat. Immunol. (2003) [Pubmed]
  14. Differential hypermethylation of SOCS genes in ovarian and breast carcinomas. Sutherland, K.D., Lindeman, G.J., Choong, D.Y., Wittlin, S., Brentzell, L., Phillips, W., Campbell, I.G., Visvader, J.E. Oncogene (2004) [Pubmed]
  15. Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin. Liedert, B., Materna, V., Schadendorf, D., Thomale, J., Lage, H. J. Invest. Dermatol. (2003) [Pubmed]
  16. Therapeutic approaches including interferon to carcinoma in situ of the bladder. Lum, B.L., Torti, F.M. Cancer Treat. Rev. (1985) [Pubmed]
  17. cis-platinum and ovarian carcinoma. In vitro chemosensitivity of cultured tumour cells from patients receiving high dose cis-platinum as first line treatment. Wilson, A.P., Ford, C.H., Newman, C.E., Howell, A. Br. J. Cancer (1987) [Pubmed]
  18. Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors. Roger, P., Daures, J.P., Maudelonde, T., Pignodel, C., Gleizes, M., Chapelle, J., Marty-Double, C., Baldet, P., Mares, P., Laffargue, F., Rochefort, H. Hum. Pathol. (2000) [Pubmed]
  19. Interleukin 11 signaling components signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) regulate human endometrial stromal cell differentiation. Dimitriadis, E., Stoikos, C., Tan, Y.L., Salamonsen, L.A. Endocrinology (2006) [Pubmed]
  20. Cloning and characterization of CIS 1b (cytokine inducible SH2-containing protein 1b), an alternative splicing form of CIS 1 gene. Jiang, C., Yu, L., Zhao, Y., Zhang, M., Liu, Q., Mao, N., Geng, Z., Zhao, S. DNA Seq. (2000) [Pubmed]
  21. Expression of SOCS genes in normal and leukemic human leukocytes stimulated by prolactin, growth hormone and cytokines. Dogusan, Z., Hooghe-Peters, E.L., Berus, D., Velkeniers, B., Hooghe, R. J. Neuroimmunol. (2000) [Pubmed]
  22. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. Ram, P.A., Waxman, D.J. J. Biol. Chem. (1999) [Pubmed]
  23. A proinflammatory cytokine response is present in the fetal placental vasculature in placental insufficiency. Wang, X., Athayde, N., Trudinger, B. Am. J. Obstet. Gynecol. (2003) [Pubmed]
  24. Cytokine-like effects of prolactin in human mononuclear and polymorphonuclear leukocytes. Dogusan, Z., Hooghe, R., Verdood, P., Hooghe-Peters, E.L. J. Neuroimmunol. (2001) [Pubmed]
  25. SOCS-3 is tyrosine phosphorylated in response to interleukin-2 and suppresses STAT5 phosphorylation and lymphocyte proliferation. Cohney, S.J., Sanden, D., Cacalano, N.A., Yoshimura, A., Mui, A., Migone, T.S., Johnston, J.A. Mol. Cell. Biol. (1999) [Pubmed]
  26. CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling. Aman, M.J., Migone, T.S., Sasaki, A., Ascherman, D.P., Zhu, M., Soldaini, E., Imada, K., Miyajima, A., Yoshimura, A., Leonard, W.J. J. Biol. Chem. (1999) [Pubmed]
  27. Unlocking pathology archives for molecular genetic studies: a reliable method to generate probes for chromogenic and fluorescent in situ hybridization. Lambros, M.B., Simpson, P.T., Jones, C., Natrajan, R., Westbury, C., Steele, D., Savage, K., Mackay, A., Schmitt, F.C., Ashworth, A., Reis-Filho, J.S. Lab. Invest. (2006) [Pubmed]
  28. 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]
  29. Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor. Dif, F., Saunier, E., Demeneix, B., Kelly, P.A., Edery, M. Endocrinology (2001) [Pubmed]
  30. The C-terminus of CIS defines its interaction pattern. Lavens, D., Ulrichts, P., Catteeuw, D., Gevaert, K., Vandekerckhove, J., Peelman, F., Eyckerman, S., Tavernier, J. Biochem. J. (2007) [Pubmed]
  31. Prolactin-induced expression of cytokine-inducible SH2 signaling inhibitors in human hematopoietic progenitors. Cwikel, S., Silvian-Drachsler, I., Prolov, L., Hooghe-Peters, E.L., Merchav, S. Exp. Hematol. (2001) [Pubmed]
  32. Mammalian protein-protein interaction trap (MAPPIT) analysis of STAT5, CIS, and SOCS2 interactions with the growth hormone receptor. Uyttendaele, I., Lemmens, I., Verhee, A., De Smet, A.S., Vandekerckhove, J., Lavens, D., Peelman, F., Tavernier, J. Mol. Endocrinol. (2007) [Pubmed]
  33. Growth hormone regulation of SOCS-2, SOCS-3, and CIS messenger ribonucleic acid expression in the rat. Tollet-Egnell, P., Flores-Morales, A., Stavréus-Evers, A., Sahlin, L., Norstedt, G. Endocrinology (1999) [Pubmed]
  34. Prognostic, predictive and therapeutic implications of HER2 in invasive epithelial ovarian cancer. Serrano-Olvera, A., Dueñas-González, A., Gallardo-Rincón, D., Candelaria, M., De la Garza-Salazar, J. Cancer Treat. Rev. (2006) [Pubmed]
  35. Molecular genetic analysis of the REST/NRSF gene in nervous system tumors. Blom, T., Tynninen, O., Puputti, M., Halonen, M., Paetau, A., Haapasalo, H., Tanner, M., Nupponen, N.N. Acta Neuropathol. (2006) [Pubmed]
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