Colorectal cancer risk is increased in shift workers with presumed circadian 
disruption. Intestinal epithelial cell proliferation is gated throughout each 
day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 
mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression 
of cyclin D and c-Myc genes that are key to proliferation control. We asked 
whether Per2 clock gene inactivation would accelerate intestinal and colonic 
tumorigenesis. The effects of PER2 on cell proliferation and beta-catenin were 
studied in colon cancer cell lines by its down-regulation following RNA 
interference. The effects of Per2 inactivation in vivo on beta-catenin and on 
intestinal and colonic polyp formation were studied in mice with Per2 mutation 
alone and in combination with an Apc mutation using polyp-prone Apc(Min/+) mice. 
Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases 
beta-catenin, cyclin D, and cell proliferation. Down-regulation of beta-catenin 
along with Per2 blocks the increase in cyclin D and cell proliferation. 
Per2(m/m) mice develop colonic polyps and show an increase in small intestinal 
mucosa beta-catenin and cyclin D protein levels compared with wild-type mice. 
Apc(Min/+)Per2(m/m) mice develop twice the number of small intestinal and 
colonic polyps, with more severe anemia and splenomegaly, compared with 
Apc(Min/+) mice. These data suggest that Per2 gene product suppresses 
tumorigenesis in the small intestine and colon by down-regulation of 
beta-catenin and beta-catenin target genes, and this circadian core clock gene 
may represent a novel target for colorectal cancer prevention and control.