Disease relevance of IKBKE

• We show IKK-i/IKKepsilon expression in primary human breast cancer specimens and carcinogen-induced mouse mammary tumors [1].

High impact information on IKBKE

• B-DNA signaling by this pathway conferred resistance to viral infection in a way dependent on both TBK1 and IKKi [2].
• TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction [3].
• Interestingly, IKK-i/IKKepsilon expression correlated with CK2alpha expression in mammary glands and breast tumors derived from MMTV-CK2alpha transgenic mice [1].
• IKK-i/IKK{epsilon} Controls Constitutive, Cancer Cell-associated NF-{kappa}B Activity via Regulation of Ser-536 p65/RelA Phosphorylation [4].
• Knockdown of IKK-i/IKKepsilon or expression of a S536A mutant form of p65 suppresses HeLa cell proliferation [4].

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

• Consistent with the activation of IKKi, expression of Nur77 in macrophages potentiates the induction of inflammatory gene expression in response to lipopolysaccharide [9].

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

• TBK-1 and IKK-i phosphorylate Ser(36) of IkappaBalpha [10].

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].

References