Beta-catenin induces beta-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 beta-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 beta-catenin destabilizes PER2 clock protein by inducing beta-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 beta-catenin induced intestinal epithelial neoplastic transformation in both mouse and man.
Yang
Xiaoming
X
Medical Chronobiology Laboratory, Dorn Research Institute, WJB Dorn Veterans Affairs Medical Center, University of South Carolina, Columbia, SC, USA.
Wood
Patricia A
PA
Ansell
Christine M
CM
Ohmori
Masami
M
Oh
Eun-Yeong
EY
Xiong
Yin
Y
Berger
Franklin G
FG
Peña
Maria Marjorette O
MM
Hrushesky
William J M
WJ
D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002940:Circadian Rhythm / Q000235:genetics*; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009687:Nuclear Proteins / Q000378:metabolism*; D056950:Period Circadian Proteins; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C421902:PER2 protein, human; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538944:Clock protein, mouse