Cells Lacking IKKα Show Nuclear Cyclin D1 Overexpression and a Neoplastic Phenotype: Role of IKKα as a Tumor Suppressor

The catalytic subunits of I kappa B kinase (IKK) complex, IKK alpha and IKK beta, are involved in activation of NF-kappa B and in mediating a variety of other biological functions. Though these proteins have a high-sequence homology, IKK alpha exhibits different functional characteristics as compared with IKK beta. Earlier, we have shown that cyclin D1 is overexpressed and predominantly localized in the nucleus of IKK alpha(-/-) cells, indicating that IKK alpha regulates turnover and subcellular distribution of cyclin D1, which is mediated by IKK alpha-induced phosphorylation of cyclin D1. Because cyclin D nuclear localization is implicated in tumor development, we examined whether the absence of IKK alpha leads to tumor development as well. In the current study, we show that IKK alpha plays a critical role in tumorigenesis. Though IKK alpha(-/-) 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 alpha(-/-) 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 alpha RNA expression level as compared with cell lines derived from normal bronchial epithelium. These results suggest that IKK alpha may function as a tumor suppressor gene. Absence of IKK alpha may induce tumorigenicity by nuclear localization of cyclin D1 and modulating the expression of genes involved in neoplastic transformation. Mol Cancer Res; 9(3); 341-9. (C) 2011 AACR.