SCF(Fbx4/alphaB-crystallin) E3 ligase: when one is not enough.

Cell cycle progression is determined by the balance of positive regulators, cyclin-dependent-protein kinases (cdks) relative to negative regulators, cyclin-dependent kinase inhibitors (ckis). D-type cyclins, (D1, D2, D3) are expressed in a tissue-specific manner and are the first cyclins to be expressed during the cell cycle. Of the three D-type cyclins, cyclin D1 is most frequently overexpressed in human cancer. The mechanisms of cyclin D1 overexpression can be attributed to gene amplification, transcriptional activation and altered protein degradation; of these, inhibition of ubiquitin-dependent proteolysis of cyclin D1 is thought to be a primary mechanism of cyclin D1 overexpression in human tumors. Because the identity of the regulators of cyclin D1 proteolysis were largely undefined until recently, it had not been possible to determine whether this regulatory network was directly targeted in primary cancer. Cyclin D1 proteolysis requires phosphorylation by GSK3beta at Thr-286; additional work recently established that p286-D1 is a substrate for the SCF(Fbx4/alphaB-crystallin) E3 ligase. This discovery has facilitated an analysis of SCF(Fbx4/alphaB-crystallin) ligase in human cancers. This recent work revealed that Fbx4 is subject to mutational inactivation in human cancer, resulting in the accumulation of cyclin D1. Molecular analysis of this ligase has revealed striking regulatory features that contribute to regulated cyclin D1 accumulation and support the idea that Fbx4 is a bona fide tumor suppressor.