Cells lacking IKK? show nuclear cyclin D1 overexpression and a neoplastic phenotype: role of IKK? as a tumor suppressor.

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

SUBMITTER: Kwak YT 

PROVIDER: S-EPMC3072035 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature