Ikappa B kinase alpha (IKKalpha ) regulates sub-cellular distribution and turnover of cyclin D1 by phosphorylation

doi:10.1074/jbc.M506206200

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Papers In Press, published online ahead of print August 15, 2005
J. Biol. Chem, 10.1074/jbc.M506206200
Submitted on June 7, 2005
Accepted on August 15, 2005

I $kappa$ B kinase $alpha$ (IKK $alpha$ ) regulates sub-cellular distribution and turnover of cyclin D1 by phosphorylation

Youn-Tae Kwak, Rui Li, Carlos Becerra, Debu Tripathy, Eugene Frenkel, and Udit N. Verma

Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390

Corresponding Author: udit.verma{at}utsouthwestern.edu

I $kappa$ B kinase $alpha$ (IKK $alpha$ ) plays a critical role in regulating cyclin D1 during the cell cycle. Analysis of IKK $alpha$ ^-/- mouse embryo fibroblast cells (MEF) showed that cyclin D1 is over-expressed and localized in the nucleus compared to parental MEF. IKK $alpha$ associates with and phosphorylates cyclin D1. Analysis on cyclin D1 mutants demonstrated that IKK $alpha$ phosphorylates cyclin D1 at threonine 286 residue (T286). Reconstitution of IKK $alpha$ in knock-out cells leads to nuclear export and increased degradation of cyclin D1. Further, RNAi-mediated knock-down of IKK $alpha$ results in similar changes as observed in IKK $alpha$ ^-/- cells. These results suggest a novel role of IKK $alpha$ in regulating sub-cellular localization and proteolysis of cyclin D1 by phosphorylation of cyclin D1 at T286, the same residue earlier found to be target for glycogen synthase kinase-3 $beta$ (GSK-3 $beta$ ) induced phosphorylation.

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IB kinase (IKK) regulates sub-cellular distribution and turnover of cyclin D1 by phosphorylation

I $kappa$ B kinase $alpha$ (IKK $alpha$ ) regulates sub-cellular distribution and turnover of cyclin D1 by phosphorylation