IκB kinase α regulates subcellular distribution and turnover of cyclin D1 by phosphorylation

IκB kinases (IKKs), IKKα and IKKβ, with a regulatory subunit IKKγ/NEMO constitute a high molecular weight IKK complex that regulates NF-κB activity. Although IKKα and IKKβ share structural and biochemical similarities, IKKα has been shown to have distinct biological roles. Here we show that IKKα plays a critical role in regulating cyclin D1 during the cell cycle. Analysis of IKKα ^-/- mouse embryo fibroblast cells showed that cyclin D1 is overexpressed and localized in the nucleus compared with parental mouse embryo fibroblasts. IKKα associates with and phosphorylates cyclin D1. Analysis on cyclin Dl mutants demonstrated that IKKα phosphorylates cyclin D1 at Thr²⁸⁶. Reconstitution of IKKα in knockout cells leads to nuclear export and increased degradation of cyclin D1. Further, RNAi-mediated knockdown of IKKα results in similar changes as observed in IKKα^-/- cells. These results suggest a novel role of IKKα in regulating subcellular localization and proteolysis of cyclin D1 by phosphorylation of cyclin D1 at Thr²⁸⁶, the same residue earlier found to be a target for glycogen synthase kinase-3β-induced phosphorylation.