Cytokine-inducible SH2-containing protein is a protein that in humans is encoded by the CISHgene.[5][6][7]CISHorthologs[8] have been identified in most mammals with sequenced genomes. CISH controls T cell receptor (TCR) signaling, and variations of CISH with certain SNPs are associated with susceptibility to bacteremia, tuberculosis and malaria.[9]
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 IL-2, IL-3, 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.[7]
CISH is induced by T cell receptor (TCR) ligation and negatively regulates it by targeting the critical signaling intermediate PLC-gamma-1 for degradation.[10] 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.
In human tumor-infiltrating lymphocytes (TIL), CISH expression has been reported to be inversely expressed with known T cell activation/exhaustion markers and regulates their expression and neoantigen reactivity. Combination therapy with checkpoint blockade synergistically results in profound tumor regressing in a pre-clinical tumor model [11]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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". Cytogenetics and Cell Genetics. 78 (3–4): 209–12. doi:10.1159/000134658. PMID9465889.
^Khor CC, Vannberg FO, Chapman SJ, Guo H, Wong SH, Walley AJ, Vukcevic D, Rautanen A, Mills TC, Chang KC, Kam KM, Crampin AC, Ngwira B, Leung CC, Tam CM, Chan CY, Sung JJ, Yew WW, Toh KY, Tay SK, Kwiatkowski D, Lienhardt C, Hien TT, Day NP, Peshu N, Marsh K, Maitland K, Scott JA, Williams TN, Berkley JA, Floyd S, Tang NL, Fine PE, Goh DL, Hill AV (Jun 2010). "CISH and susceptibility to infectious diseases". The New England Journal of Medicine. 362 (22): 2092–101. doi:10.1056/NEJMoa0905606. PMC3646238. PMID20484391. [Free Text]
Kile BT, Schulman BA, Alexander WS, Nicola NA, Martin HM, Hilton DJ (May 2002). "The SOCS box: a tale of destruction and degradation". Trends in Biochemical Sciences. 27 (5): 235–41. doi:10.1016/S0968-0004(02)02085-6. PMID12076535.
Jiang C, Yu L, Zhao Y, Zhang M, Liu Q, Mao N, Geng Z, Zhao S (2000). "Cloning and characterization of CIS 1b (cytokine inducible SH2-containing protein 1b), an alternative splicing form of CIS 1 gene". DNA Sequence. 11 (1–2): 149–54. doi:10.3109/10425170009033983. PMID10902923. S2CID7986394.
Dogusan Z, Hooghe-Peters EL, Berus D, Velkeniers B, Hooghe R (Sep 2000). "Expression of SOCS genes in normal and leukemic human leukocytes stimulated by prolactin, growth hormone and cytokines". Journal of Neuroimmunology. 109 (1): 34–9. doi:10.1016/S0165-5728(00)00300-3. PMID10969179. S2CID23752435.
Yousefi S, Cooper PR, Mueck B, Potter SL, Jarai G (Oct 2000). "cDNA representational difference analysis of human neutrophils stimulated by GM-CSF". Biochemical and Biophysical Research Communications. 277 (2): 401–9. doi:10.1006/bbrc.2000.3678. PMID11032736.