1147

CHUK

IKBKA|IKK-alpha|IKK1|IKKA|NFKBIKA|TCF16;conserved helix-loop-helix ubiquitous kinase;CHUK;conserved helix-loop-helix ubiquitous kinase

I-kappa-B kinase 1|I-kappa-B kinase-alpha|IKK-a kinase|IkB kinase alpha subunit|Nuclear factor NFkappaB inhibitor kinase alpha|TCF-16|inhibitor of nuclear factor kappa-B kinase subunit alpha|transcription factor 16

10q24-q25

protein-coding

Count: 1; Generif

The molecular mechanism by which IkappaB kinase 1 (IKK1) regulates epidermal differentiation and tumor suppression in the skin is not well understood. As two major regulatory signaling pathways that regulate epidermal homeostasis and differentiation, the p63 and Notch pathways were examined in Ikk1 mutant epidermis and keratinocytes. Ikk1 inactivation in keratinocytes resulted in increased p63 expression and repression of Notch signaling. The impaired differentiation of Ikk1(-/-) keratinocytes was partially rescued by overexpression of the active form of the Notch1 receptor, the Notch intracellular domain (NICD). In contrast, knockdown of p63 expression by RNA interference was unable to rescue the defect. These results suggest that, in the mammalian skin, IKK1 functions as a differentiation regulator and tumor suppressor through the Notch signaling pathway.CI - Copyright (c) 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The catalytic subunits of IkappaB kinase (IKK) complex, IKKalpha and IKKbeta, are involved in activation of NF-kappaB and in mediating a variety of other biological functions. Though these proteins have a high-sequence homology, IKKalpha exhibits different functional characteristics as compared with IKKbeta. Earlier, we have shown that cyclin D1 is overexpressed and predominantly localized in the nucleus of IKKalpha(-/-) cells, indicating that IKKalpha regulates turnover and subcellular distribution of cyclin D1, which is mediated by IKKalpha-induced phosphorylation of cyclin D1. Because cyclin D nuclear localization is implicated in tumor development, we examined whether the absence of IKKalpha leads to tumor development as well. In the current study, we show that IKKalpha plays a critical role in tumorigenesis. Though IKKalpha(-/-) MEF cells show a slower anchorage-dependent growth, they are clonogenic in soft agar. These cells are tumorigenic in nude mice. Microarray analysis of IKKalpha(-/-) cells indicates a differential expression of genes involved in proliferation and apoptosis. Furthermore, analysis of microarray data of human lung cancer cell lines revealed decreased IKKalpha RNA expression level as compared with cell lines derived from normal bronchial epithelium. These results suggest that IKKalpha may function as a tumor suppressor gene. Absence of IKKalpha may induce tumorigenicity by nuclear localization of cyclin D1 and modulating the expression of genes involved in neoplastic transformation.