Oncogene database

9641

IKBKE

inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon;IKBKE;inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon

I-kappa-B kinase epsilon|IKK-epsilon|IKK-related kinase epsilon|inducible I kappa-B kinase|inducible IkappaB kinase|inhibitor of nuclear factor kappa-B kinase subunit epsilon

1q32.1

protein-coding

The karyotypic chaos exhibited by human epithelial cancers complicates efforts to identify mutations critical for malignant transformation. Here we integrate complementary genomic approaches to identify human oncogenes. We show that activation of the ERK and phosphatidylinositol 3-kinase (PI3K) signaling pathways cooperate to transform human cells. Using a library of activated kinases, we identify several kinases that replace PI3K signaling and render cells tumorigenic. Whole genome structural analyses reveal that one of these kinases, IKBKE (IKKepsilon), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKepsilon expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKepsilon activates the nuclear factor-kappaB (NF-kappaB) pathway in both cell lines and breast cancers. These observations suggest a mechanism for NF-kappaB activation in breast cancer, implicate the NF-kappaB pathway as a downstream mediator of PI3K, and provide a framework for integrated genomic approaches in oncogene discovery.

The noncanonical IKK family member IKKepsilon is essential for regulating antiviral signaling pathways and is a recently discovered breast cancer oncoprotein. Although several IKKepsilon targets have been described, direct IKKepsilon substrates necessary for regulating cell transformation have not been identified. Here, we performed a screen for putative IKKepsilon substrates using an unbiased proteomic and bioinformatic approach. Using a positional scanning peptide library assay, we determined the optimal phosphorylation motif for IKKepsilon and used bioinformatic approaches to predict IKKepsilon substrates. Of these potential substrates, serine 418 of the tumor suppressor CYLD was identified as a likely site of IKKepsilon phosphorylation. We confirmed that CYLD is directly phosphorylated by IKKepsilon and that IKKepsilon phosphorylates serine 418 in vivo. Phosphorylation of CYLD at serine 418 decreases its deubiquitinase activity and is necessary for IKKepsilon-driven transformation. Together, these observations define IKKepsilon and CYLD as an oncogene-tumor suppressor network that participates in tumorigenesis.

BACKGROUND: Advanced prostate cancer (PCa) remains a one of the leading causes of cancer related death and is often due to the progression from a hormone sensitive (HS) to a castrate resistant (CR) state for which therapeutic alternatives remain palliative. Molecular events involved in the progression to CR-PCa remain largely unknown. A previous study reported significantly higher levels of Ikappa-B kinase-epsilon (IKKepsilon) expression in CR compared to androgen-responsive cell lines. In the present study, we evaluate IKKepsilon expression in human prostate tissue. METHODS: In order to evaluate the modulation of IKKepsilon expression in PCa tissue IKKepsilon immunostaining was performed on paraffin-embedded prostate tissue microarrays containing cores from normal tissues (n = 47), non-malignant tissues adjacent to the tumor (n = 53), prostatic intraepithelial neoplasia (PIN) (n = 28), HS (n = 62), and CR tumors (n = 31). RESULTS: We found a low cytoplasmic expression of IKKepsilon in non-malignant tissue. HS tumors showed a significant increase in cytoplasmic IKKepsilon expression compared to non-malignant tissues. CR tissues presented the highest cytoplasmic IKKepsilon expression levels. We also report, for the first time, the presence of a nuclear localization of IKKepsilon in prostate epithelial cells, in particular we observed an increase of IKKepsilon nuclear localization in HS malignant tissues. Finally, we found a strong link between an increase of IKKepsilon cytoplasmic expression in PCa and metastatic progression. CONCLUSION: This study strongly suggests the role of IKKepsilon as a PCa oncogene that may be involved in the emergence of a CR state.

BACKGROUND/AIMS: The expression of estrogen receptor-alpha (ERalpha) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERalpha-36 has been identified as a novel variant of ER-alpha. ERalpha-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. The noncanonical IKK family member IKKepsilon is essential for regulating antiviral signaling pathways and is recently discovered as a breast cancer oncogene. IKKepsilon interacts with and phosphorylates ERalpha on serine 167, induces ERalpha transactivation activity and enhances ERalpha binding to DNA in ER-positive breast cancer cells. However, the correlation between IKKepsilon and the ERalpha-36 signaling pathway in ER-negative breast cancer cells remains unclear. METHODS AND RESULTS: In this study, we show that IKKepsilon interacts with ERalpha-36 and increases its expression in breast cancer cells. As shown by western blot assays, the upregulation of ERalpha-36 by IKKepsilon was significant. In MDA-MB-231 cells which are ER-negative, IKKepsilon was able to increase the expression of ERalpha-36 in a dose-dependent manner, and the RNA interference assay indicated the correlation between IKKepsilon and ERalpha-36 expression. Moreover, IKKepsilon enhanced the growth of MDA-MB-231 and MDA-MB-436 cells. CONCLUSIONS: These results suggest that IKKepsilon increases ERalpha-36 expression and is involved in ERalpha-36 mediated non-genomic estrogen signaling.