title: Cells lacking IKKα show nuclear cyclin D1 overexpression and a neoplastic phenotype: role of IKKα as a tumor suppressor.
abstract: The catalytic subunits of IκB kinase (IKK) complex, IKKα and IKKβ, are involved in activation of NF-κB and in mediating a variety of other biological functions. Though these proteins have a high-sequence homology, IKKα exhibits different functional characteristics as compared with IKKβ. Earlier, we have shown that cyclin D1 is overexpressed and predominantly localized in the nucleus of IKKα(-/-) cells, indicating that IKKα regulates turnover and subcellular distribution of cyclin D1, which is mediated by IKKα-induced phosphorylation of cyclin D1. Because cyclin D nuclear localization is implicated in tumor development, we examined whether the absence of IKKα leads to tumor development as well. In the current study, we show that IKKα plays a critical role in tumorigenesis. Though IKKα(-/-) MEF cells show a slower anchorage-dependent growth, they are clonogenic in soft agar. These cells are tumorigenic in nude mice. Microarray analysis of IKKα(-/-) 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 IKKα RNA expression level as compared with cell lines derived from normal bronchial epithelium. These results suggest that IKKα may function as a tumor suppressor gene. Absence of IKKα may induce tumorigenicity by nuclear localization of cyclin D1 and modulating the expression of genes involved in neoplastic transformation.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Youn-Tae
authors.initials: YT
authors.lastname: Kwak
authors.forename: Sofyan M
authors.initials: SM
authors.lastname: Radaideh
authors.forename: Lianghao
authors.initials: L
authors.lastname: Ding
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Eugene
authors.initials: E
authors.lastname: Frenkel
authors.forename: Michael D
authors.initials: MD
authors.lastname: Story
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: John
authors.initials: J
authors.lastname: Minna
authors.forename: Udit N
authors.initials: UN
authors.lastname: Verma
mesh_terms: D000818:Animals; D017209:Apoptosis; D015197:Carcinogenicity Tests / Q000379:methods; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis / Q000379:methods; D010641:Phenotype; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D019938:Cyclin D1; D051550:I-kappa B Kinase