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Gene Review

IKBKE  -  inhibitor of kappa light polypeptide gene...

Homo sapiens

Synonyms: I-kappa-B kinase epsilon, IKK-E, IKK-epsilon, IKK-i, IKKE, ...
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Disease relevance of IKBKE


High impact information on IKBKE


Biological context of IKBKE

  • Dose-response studies showed that as little as 1 ng/ml of TNFalpha increased IKK-i gene expression [5].
  • These results suggest that both TBK1 and IKKi are required for innate immune activation by B-DNA, which might be important in antiviral innate immunity and other DNA-associated immune disorders [2].
  • NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation [6].
  • FNBP2 gene was linked to IKBKE and NORE1 genes on human chromosome 1q32 [7].
  • Here, we demonstrate that IKK-i/IKKepsilon is expressed in a number of cancer cells and is involved in regulating NF-kappaB activity through its ability to control basal/constitutive, but not cytokine-induced, p65/RelA phosphorylation at Ser-536, a modification proposed to contribute to the transactivation function of NF-kappaB [4].

Anatomical context of IKBKE

  • These data for the first time characterize the promoter region and provide further insights into the transcriptional regulation of IKKi in human chondrocytes and other cell types [8].
  • Several inflammatory agents have been shown to induce the expression of the IKKi gene in macrophages and other cell types but the mechanism is unknown [8].
  • We have found that the IKKi expression was constitutive in human chondrocytes from OA cartilage and a human chondrocytic cell line C28/I2 but was up-regulated by the inflammatory cytokines TNFalpha or IL-1betain an NFkappaB-dependent manner [8].

Associations of IKBKE with chemical compounds


Physical interactions of IKBKE

  • RESULTS: I-TRAF/TANK was isolated as a molecule that interacts specifically with inducible IkappaB kinase (IKK-i) by the yeast two-hybrid screening procedure [6].

Enzymatic interactions of IKBKE


Regulatory relationships of IKBKE

  • IKK-i over-expression also induced c-Jun N-terminal kinase [6].
  • TNF-alpha also strongly enhanced IKK epsilon mRNA and protein expression [11].
  • We have generated tetracycline-inducible stable cell lines that express a wild type or kinase-inactive mutant form of IKK-i. Our data suggest that expression of IKK-i can activate both NFkappaB and IRF3, leading to the production of several cytokines including interferon beta [12].
  • IKK-i most likely acts upstream of IKK2 to activate NFkappaB in these cells since expression of the kinase-inactive version of IKK-i did not inhibit TNFalpha mediated production of inflammatory cytokines [12].

Other interactions of IKBKE

  • Here we show that TBK1 and IKK epsilon synergize with TANK to promote interaction with the IKKs [13].
  • IL-1 also significantly increased IKK-i gene expression [5].
  • We have recently identified a cytokine inducible IKK-i, a kinase related to IKK-alpha and -beta [6].
  • IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines [12].
  • Experiments suggest that LGP2 can compete with the kinase IKKi (also known as IKKepsilon) for a common interaction site on IPS-1 [14].

Analytical, diagnostic and therapeutic context of IKBKE

  • We found that IKKi core promoter was TATA-less and by using PCR generated deletion mutants of the PPR we found that the cis-elements responsible for basal transcriptional activity were located between -51 and -100 bp upstream of the TSS while the cytokine response elements were located distally between -501 and -1000 bp upstream of the TSS [8].
  • The results of site-directed mutagenesis revealed that the kappaB site located between -833 and -847 bp upstream of the TSS was biologically functional and required for cytokine-induced IKKi promoter activity in human chondrocytes and HeLa cells [8].


  1. Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Eddy, S.F., Guo, S., Demicco, E.G., Romieu-Mourez, R., Landesman-Bollag, E., Seldin, D.C., Sonenshein, G.E. Cancer Res. (2005) [Pubmed]
  2. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Ishii, K.J., Coban, C., Kato, H., Takahashi, K., Torii, Y., Takeshita, F., Ludwig, H., Sutter, G., Suzuki, K., Hemmi, H., Sato, S., Yamamoto, M., Uematsu, S., Kawai, T., Takeuchi, O., Akira, S. Nat. Immunol. (2006) [Pubmed]
  3. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K.J., Takeuchi, O., Akira, S. Nat. Immunol. (2005) [Pubmed]
  4. IKK-i/IKK{epsilon} Controls Constitutive, Cancer Cell-associated NF-{kappa}B Activity via Regulation of Ser-536 p65/RelA Phosphorylation. Adli, M., Baldwin, A.S. J. Biol. Chem. (2006) [Pubmed]
  5. Expression and regulation of inducible IkappaB kinase (IKK-i) in human fibroblast-like synoviocytes. Aupperle, K.R., Yamanishi, Y., Bennett, B.L., Mercurio, F., Boyle, D.L., Firestein, G.S. Cell. Immunol. (2001) [Pubmed]
  6. NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation. Nomura, F., Kawai, T., Nakanishi, K., Akira, S. Genes Cells (2000) [Pubmed]
  7. FNBP2 gene on human chromosome 1q32.1 encodes ARHGAP family protein with FCH, FBH, RhoGAP and SH3 domains. Katoh, M., Katoh, M. Int. J. Mol. Med. (2003) [Pubmed]
  8. Genomic structure and functional characterization of the promoter region of human IkappaB kinase-related kinase IKKi/IKKvarepsilon gene. Wang, N., Ahmed, S., Haqqi, T.M. Gene (2005) [Pubmed]
  9. Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77. Pei, L., Castrillo, A., Tontonoz, P. Mol. Endocrinol. (2006) [Pubmed]
  10. Kinetic mechanisms of IkappaB-related kinases (IKK) inducible IKK and TBK-1 differ from IKK-1/IKK-2 heterodimer. Huynh, Q.K., Kishore, N., Mathialagan, S., Donnelly, A.M., Tripp, C.S. J. Biol. Chem. (2002) [Pubmed]
  11. Tumor necrosis factor alpha enhances influenza A virus-induced expression of antiviral cytokines by activating RIG-I gene expression. Matikainen, S., Sirén, J., Tissari, J., Veckman, V., Pirhonen, J., Severa, M., Sun, Q., Lin, R., Meri, S., Uzé, G., Hiscott, J., Julkunen, I. J. Virol. (2006) [Pubmed]
  12. IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines. Sankar, S., Chan, H., Romanow, W.J., Li, J., Bates, R.J. Cell. Signal. (2006) [Pubmed]
  13. Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases. Chariot, A., Leonardi, A., Muller, J., Bonif, M., Brown, K., Siebenlist, U. J. Biol. Chem. (2002) [Pubmed]
  14. RNA- and Virus-Independent Inhibition of Antiviral Signaling by RNA Helicase LGP2. Komuro, A., Horvath, C.M. J. Virol. (2006) [Pubmed]
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