BioProject

We report that Rev-erbα is targeted for ubiquitination and subsequent degradation by the F-box protein Fbxw7α, and identify the cyclin-dependent kinase 1 (Cdk1)-mediated phosphorylation of threonine 275 as necessary for the recruitment of the Fbxw7-dependent E3 ligase complex. More...

We report that Rev-erbα is targeted for ubiquitination and subsequent degradation by the F-box protein Fbxw7α, and identify the cyclin-dependent kinase 1 (Cdk1)-mediated phosphorylation of threonine 275 as necessary for the recruitment of the Fbxw7-dependent E3 ligase complex. In vitro, inhibition of Cdk1 kinase activity or mutation of T275 is sufficient to disrupt the Fbxw7-mediated Rev-erbα degradation pathway. Moreover, genetic disruption of Fbxw7 in mouse liver dramatically alters the circadian expression of core clock genes and perturbs whole body lipid and glucose levels. These results reveal an additional level of regulation required for maintaining circadian rhythmicity, and reveal the essential roles of post-translational modifications in the coordination of the circadian clocks and metabolism through regulation of nuclear receptor protein stability. Less...