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Gene Review

TRAF3IP2  -  TRAF3 interacting protein 2

Homo sapiens

Synonyms: ACT1, Adapter protein CIKS, C6orf2, C6orf4, C6orf5, ...
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Disease relevance of TRAF3IP2

  • The data in ulcerative colitis (UC) are conflicting and we should await the results of 2 large controlled trials (ACT1 and ACT2) to position infliximab in the treatment of UC [1].
  • Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC beta-lactamase, and the foss of an outer membrane protein [2].
  • Insertion of an internal DNA fragment into the act1 gene, which encodes one of several sigma(54)-activator proteins in Myxococcus xanthus, produced a mutant defective in fruiting body development [3].
  • We have found that addition of Act1 intron 1 to the transcription unit of a Gus reporter gene under control of the cauliflower mosaic virus (CaMV) 35S promoter stimulated GUS activity more than 10-fold in transformed rice cells [4].
  • In keeping with this concept, we were able to demonstrate that in the majority of cases of Hodgkin's disease the interleukin-2 receptor (IL2-R) was detectable on H-RS-cells by three monoclonal antibodies (anti-Tac, Tü69 and ACT-1) with the sensitive alkaline phosphatase anti-alkaline phosphatase (APAAP) tissue staining procedure [5].

High impact information on TRAF3IP2

  • We have identified a conserved sequence segment in transmembrane receptors (including SEFs, IL17Rs) and soluble factors (including CIKS/ACT1) in eukaryotes and bacteria - the SEFIR domain [6].
  • The 5' region of the rice actin 1 gene (Act1) has been developed as an efficient regulator of foreign gene expression in transgenic rice plants [7].
  • Fusions that lack this Act1 intron showed no detectable GUS activity in transient assays of transformed rice protoplasts [8].
  • We conclude that Act1 plays an important role in CD40-mediated signaling in epithelial cells [9].
  • Role of NF kappa B activator Act1 in CD40-mediated signaling in epithelial cells [9].

Biological context of TRAF3IP2

  • We conclude that the proximal 5'-flanking region of CIKS gene contains a functional promoter and binding sites for nuclear proteins leading to its basal transcription [10].
  • The transcription start site of CIKS mRNA was mapped both by primer extension and by a polymerase chain reaction (PCR)-based strategy [10].
  • The aim of this study is to identify and characterize the promoter region of CIKS gene and to analyse the regulation of its expression by different cytokines [10].
  • Deletion analysis identified a sequence from -464 to -220 bp of the 5'-flanking region of CIKS gene essential for basal promoter activity in MDCK cells [10].
  • This feature and the antisense polarity of transcription suggest that C6UAS could play a regulatory role on the expression of C6orf4, as indicated by a significant decrease of endogenous C6orf4 expression after transfection of C6UAS cDNA in human fibroblasts [11].

Anatomical context of TRAF3IP2

  • Competitive reverse transcriptase-PCR, Northern and Western blot assays showed that different cytokines, such as tumor necrosis factor (TNF)-alpha, Interleukin (IL)-1beta and transforming growth factor (TGF)-beta, dramatically increased CIKS mRNA expression in HeLa cells [10].
  • In contrast, both the spliced and full-length Act1 templates were detected in a variety of human cancer cell lines [12].
  • We demonstrated further that only the spliced Act1 was detected in cDNA libraries derived from human fetal brain, liver, leukocytes, and bone marrow [12].
  • Notably, the dominant amounts of the spliced Act1 over the full-length Act1 were amplified from both the cancer cell mRNAs and the stimulated endothelial cell mRNAs [12].
  • Northern blots probed with a segment from the 3' UTR of act1 showed a single band of approx. 1.6 kb in poly(A)+ mRNAs from epidermis, limb bud or claw muscle and in total RNAs from ovary and gill, and two bands of approx. 1.6 and 1.8 kb in total RNA from midgut gland [13].

Associations of TRAF3IP2 with chemical compounds

  • Cycloheximide superinduces the Act1 mRNA, whereas actinomycin D completely abolishes the Act1 mRNA, indicating that the induction of Act1 mRNA is at the transcriptional level and does not require protein synthesis [14].
  • Surprisingly, soluble mAb 18D3 inhibited maximal proliferation induced by the costimulatory alpha 4 beta 7-specific mAb ACT-1 by 40%, thus demonstrating that one integrin subfamily can regulate the activity of another [15].
  • This work demonstrates that in addition to resistance to cephamycins, imipenem resistance can occur in K. pneumoniae when a high level of the ACT-1 beta-lactamase is produced in combination with the loss of a major outer membrane protein [2].
  • Furthermore, the expression of the pin2-Act1 intron-Gus fusion gene in transgenic rice plants can be systemically induced by both methyl jasmonate (MJ) and the phytohormone abscisic acid (ABA) [16].
  • The expression of 3beta-hydroxysteroid dehydrogenase was observed in the ACT-1 cells as well as in normal human adrenal glands [17].

Physical interactions of TRAF3IP2

  • CIKS may help to connect upstream signaling events to IKK and SAPK/JNK modules [18].
  • The ACT-1 mAb only partially blocked NK cell binding to FN38, but in combination with the anti-beta 7 mAb LIAI 2, NK cell binding to FN38 was completely inhibited [19].

Regulatory relationships of TRAF3IP2

  • When ectopically expressed, CIKS stimulates IKK and SAPK/JNK kinases and it transactivates an NF-kappaB-dependent reporter [18].
  • We have investigated the protein binding characteristics and functional importance of the ACT-1-activating region of the IL-3 promoter [20].
  • These characteristics make the ACT-1 site analogous to the activating ARRE-1 site in the IL-2 promoter [20].

Other interactions of TRAF3IP2

  • We have recently identified a novel gene, named CIKS (Connection to IKK-complex and SAPK), able to activate the transcription factor NF-kappaB, after interaction with the regulatory subunit NEMO/IKKgamma of IKK complex, and the stress-activated protein kinase (SAPK)/JNK [10].
  • C6UAS overlaps the second exon of C6orf4, where the start codon of protein isoform 1 is located [11].
  • P53 protein expression differed in OCUT-1 and in ACT-1, though the levels stayed constant irrespective of ligand exposure in both cell lines [21].
  • Some of the steroidogenically active human adrenocortical cells (NCI-H295R) were weakly positive for GATA-4, whereas steroidogenically inactive cells (ACT-1) were totally GATA-4 negative [22].
  • However, the ACT 1 and ACT 2 trials were large, randomised and placebo-controlled, and have shown that infliximab is significantly more efficacious than placebo in treating both corticosteroid-responsive and -refractory moderate to severe UC [23].

Analytical, diagnostic and therapeutic context of TRAF3IP2

  • Promoter sequence analyses identified putative IFN regulatory factor (IRF)-1, C/EBP-beta, and AP-1 transcription factor binding sites in the Act1 promoter [14].
  • Southern blotting revealed that the gene encoding ACT-1 was on a large plasmid in some of the K. pneumoniae strains as well as on the chromosomes of all of the strains, suggesting that the gene is located on an easily mobilized element [2].


  1. Optimizing anti-TNF treatment in inflammatory bowel disease. Rutgeerts, P., Van Assche, G., Vermeire, S. Gastroenterology (2004) [Pubmed]
  2. Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC beta-lactamase, and the foss of an outer membrane protein. Bradford, P.A., Urban, C., Mariano, N., Projan, S.J., Rahal, J.J., Bush, K. Antimicrob. Agents Chemother. (1997) [Pubmed]
  3. A sigma(54) activator protein necessary for spore differentiation within the fruiting body of Myxococcus xanthus. Gorski, L., Gronewold, T., Kaiser, D. J. Bacteriol. (2000) [Pubmed]
  4. Construction of expression vectors based on the rice actin 1 (Act1) 5' region for use in monocot transformation. McElroy, D., Blowers, A.D., Jenes, B., Wu, R. Mol. Gen. Genet. (1991) [Pubmed]
  5. Immunoprecipitation of the interleukin-2 receptor from Hodgkin's disease derived cell lines by monoclonal antibodies. Schwarting, R., Gerdes, J., Ziegler, A., Stein, H. Hematological oncology. (1987) [Pubmed]
  6. The STIR-domain superfamily in signal transduction, development and immunity. Novatchkova, M., Leibbrandt, A., Werzowa, J., Neubüser, A., Eisenhaber, F. Trends Biochem. Sci. (2003) [Pubmed]
  7. Analysis of rice Act1 5' region activity in transgenic rice plants. Zhang, W., McElroy, D., Wu, R. Plant Cell (1991) [Pubmed]
  8. Isolation of an efficient actin promoter for use in rice transformation. McElroy, D., Zhang, W., Cao, J., Wu, R. Plant Cell (1990) [Pubmed]
  9. Role of NF kappa B activator Act1 in CD40-mediated signaling in epithelial cells. Qian, Y., Zhao, Z., Jiang, Z., Li, X. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  10. Promoter identification of CIKS, a novel NF-kappaB activating gene, and regulation of its expression. Pacifico, F., Barone, C., Mellone, S., Di Jeso, B., Consiglio, E., Formisano, S., Vito, P., Leonardi, A. Gene (2003) [Pubmed]
  11. Cloning and characterization of two overlapping genes in a subregion at 6q21 involved in replicative senescence and schizophrenia. Morelli, C., Magnanini, C., Mungall, A.J., Negrini, M., Barbanti-Brodano, G. Gene (2000) [Pubmed]
  12. Identification of alternatively spliced Act1 and implications for its roles in oncogenesis. Xia, Y.F., Li, Y.D., Li, X., Geng, J.G. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  13. Actin-encoding cDNAs and gene expression during the intermolt cycle of the Bermuda land crab Gecarcinus lateralis. Varadaraj, K., Kumari, S.S., Skinner, D.M. Gene (1996) [Pubmed]
  14. IFN regulatory factor-1 is required for the up-regulation of the CD40-NF-kappa B activator 1 axis during airway inflammation. Zhao, Z., Qian, Y., Wald, D., Xia, Y.F., Geng, J.G., Li, X. J. Immunol. (2003) [Pubmed]
  15. Specific inhibition of T lymphocyte coactivation by triggering integrin beta 1 reveals convergence of beta 1, beta 2, and beta 7 signaling pathways. Woodside, D.G., Teague, T.K., McIntyre, B.W. J. Immunol. (1996) [Pubmed]
  16. Systemic induction of a potato pin2 promoter by wounding, methyl jasmonate, and abscisic acid in transgenic rice plants. Xu, D., McElroy, D., Thornburg, R.W., Wu, R. Plant Mol. Biol. (1993) [Pubmed]
  17. Characterization of a newly established cell line derived from human adrenocortical carcinoma. Ueno, M., Nakashima, J., Akita, M., Ban, S.I., Nakanoma, T., Iida, M., Deguchi, N. International journal of urology : official journal of the Japanese Urological Association. (2001) [Pubmed]
  18. CIKS, a connection to Ikappa B kinase and stress-activated protein kinase. Leonardi, A., Chariot, A., Claudio, E., Cunningham, K., Siebenlist, U. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  19. Expression and function of alpha 4/beta 7 integrin on human natural killer cells. Pérez-Villar, J.J., Zapata, J.M., Melero, I., Postigo, A., Sánchez-Madrid, E., López-Botet, M. Immunology (1996) [Pubmed]
  20. Interleukin-3 expression by activated T cells involves an inducible, T-cell-specific factor and an octamer binding protein. Davies, K., TePas, E.C., Nathan, D.G., Mathey-Prevot, B. Blood (1993) [Pubmed]
  21. Peroxisome proliferator-activated receptor gamma activation induces cell cycle arrest via the p53-independent pathway in human anaplastic thyroid cancer cells. Chung, S.H., Onoda, N., Ishikawa, T., Ogisawa, K., Takenaka, C., Yano, Y., Hato, F., Hirakawa, K. Jpn. J. Cancer Res. (2002) [Pubmed]
  22. Transcription factors GATA-4 and GATA-6 in human adrenocortical tumors. Kiiveri, S., Liu, J., Heikkilä, P., Arola, J., Lehtonen, E., Voutilainen, R., Heikinheimo, M. Endocr. Res. (2004) [Pubmed]
  23. Anti-tumour necrosis factor therapy for ulcerative colitis : evidence to date. Thukral, C., Cheifetz, A., Peppercorn, M.A. Drugs (2006) [Pubmed]
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