β -Catenin Induces β-TrCP-Mediated PER2 Degradation Altering Circadian Clock Gene Expression in Intestinal Mucosa of ApcMin/ Mice

Proliferation of intestinal epithelial cells is rhythmic throughout the day. This temporal organization occurs through the interaction between the endogenous peripheral circadian clock and pathways controlling cell cycle progression. Per2, a core clock gene with tumour suppresser function, is critical to clock function and to the regulation of cellular proliferation. Circadian disruption, which increases colon cancer incidence, may do so by deregulating clock controlled epithelial cell proliferation. Increased expression of -catenin is a contributing cause of most familial and spontaneous human colon cancer and the cause of multiple intestinal neoplasia of the Apc(Min/) mouse. Here we report that increased -catenin destabilizes PER2 clock protein by inducing TrCP, an F-box protein of SCF ubiquitin E3 ligase. In the intestinal mucosa of the Apc(Min/) mouse, the decrease in PER2 protein levels is associated with altered circadian rhythms of clock genes, Per1 and Per2, and clock controlled genes, Dbp and Wee1. These findings suggest that disruption of the peripheral intestinal circadian clock may be intimately involved in -catenin induced intestinal epithelial neoplastic transformation in both mouse and man.