Mutations in Fbx4 inhibit dimerization of the SCFFbx4 ligase and contribute to cyclin D1 overexpression in human cancer

SCFFbx4 was recently identified as the E3 ligase for cyclin D1. We now describe cell-cycle-dependent phosphorylation and dimerization of Fbx4 that is regulated by GSK3 beta and is defective in human cancer. We present data demonstrating that a pathway involving Ras-Akt-GSK3 beta controls the temporal phosphorylation and dimerization of the SCFFbx4 E3 ligase. Inhibition of Fbx4 activity results in accumulation of nuclear cyclin D1 and oncogenic transformation. The importance of this regulatory pathway for normal cell growth is emphasized by the prevalence of mutations in Fbx4 in human cancer that impair dimerization. Collectively, these data reveal that inactivation of the cyclin D1 E3 ligase likely contributes to cyclin D1 overexpression in a significant fraction of human cancer.