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M403042200v1
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Papers In Press, published online ahead of print April 9, 2004
J. Biol. Chem, 10.1074/jbc.M403042200
Submitted on March 18, 2004
Revised on April 9, 2004
Accepted on April 9, 2004

Mirk/dyrk1B kinase destabilizes cyclin D1 by phosphorylation at threonine 288

Yonglong Zou, Daina Z. Ewton, Xiaobing Deng, Stephen E. Mercer, and Eileen Friedman

Pathology Dept., Upstate Medical Univ-State Univ New York, Syracuse, NY 13210

Corresponding Author: friedmae{at}upstate.edu

Phosphorylation of cyclin D1 at threonine 286 by glycogen synthase kinase 3beta has been shown to be required for cyclin D1's ubiquitination and nuclear export, and its subsequent degradation in the proteasome. Mutation of the nearby residue threonine 288 to nonphosphorylatable alanine has also been shown to reduce the ubiquitination of cyclin D1, suggesting that phosphorylation at threonine 288 may also lead to degradation of cyclin D1. We now demonstrate that the G0/G1-active, arginine-directed protein kinase Mirk/dyrk1B binds to cyclin D1 and phosphorylates cyclin D1 at threonine 288 in vivo, and that the cyclin D1-T288A construct is more stable than wild-type cyclin D1. Transient over-expression of Mirk in nontransformed Mv1Lu lung epithelial cells blocked cells in G0/G1. Depletion of endogenous Mirk by RNA interference increased cyclin D1 protein levels, but not mRNA levels, indicating that Mirk destabilizes cyclin D1 protein. Destabilization was confirmed by induction of a stable Mirk transfectant of Mv1Lu cells, which blocked cell migration (Zou Y et al, J Biol Chem 278: 49573), and caused a decrease in the half-life of endogenous cyclin D1, concomitant with an increase in Mirk expression. In vitro cyclin D1 was phosphorylated in an additive fashion by Mirk and GSK3beta . Mirk phosphorylated cyclin D1 mutated at the GSK3beta phosphorylation site, and was capable of phosphorylating cyclin D1 in the presence of the GSK3beta inhibitor LiCl. Mirk may function together with GSK3beta to assist cell arrest in G0/G1 by destabilizing cyclin D1.


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