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Journal of Biochemistry Advance Access originally published online on December 23, 2008
Journal of Biochemistry 2009 145(3):289-297; doi:10.1093/jb/mvn167
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© The Authors 2008. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

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

Xiaoming Yang1, Patricia A. Wood1,2, Christine M. Ansell1, Masami Ohmori1, Eun-Yeong Oh1, Yin Xiong1,2, Franklin G. Berger4,5, Maria Marjorette O. Peña4,5 and William J.M. Hrushesky1,3,*

1Medical Chronobiology Laboratory, Dorn Research Institute, WJB Dorn Veterans Affairs Medical Center; 2Department of Pathology, Department of Microbiology, and Department of Immunology; 3Cell Developmental Biology and Anatomy, School of Medicine; 4Department of Biological Sciences, College of Arts and Sciences; and 5Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA

*To whom correspondence addressed. Tel: +1-803-647-5654, Fax: +1-803-647-5656, E-mail: william.hrushesky{at}va.gov

Received September 10, 2008; Accepted November 21, 2008


  Abstract

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 β-catenin is a contributing cause of most familial and spontaneous human colon cancer and the cause of multiple intestinal neoplasia of the ApcMin/+ mouse. Here we report that increased β-catenin destabilizes PER2 clock protein by inducing β–TrCP, an F-box protein of SCF ubiquitin E3 ligase. In the intestinal mucosa of the ApcMin/+ 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 β-catenin induced intestinal epithelial neoplastic transformation in both mouse and man.

Key Words: circadian, colon cancer, Per2, β-catenin, β-TrCP

Abbreviations: APC, adenomatous polyposis coli gene; ApcMin/+, heterozygous Min (multiple intestinal neoplasia) mutation of the APC gene; ATCC, The American Type Culture Collection; BMAL1/Bmal1, brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like core circadian clock protein/gene; CHX, cycloheximide; CLOCK, circadian locomotor output cycles kaput; CRY/Cry, Cryptochrome protein/gene; DD, 24h constant darkness lighting condition; Dbp, albumin D-box binding protein gene; FBS, fetal bovine serum; Gapdh, glyceraldehyde-3-phosphate dehydrogenase gene; GFP, green fluorescent protein; GSK-3β, glycogen synthase kinase 3-beta; HALO, Hours After Lights On; LD, 12h light 12h dark lighting condition; NP-40, nonyl phenoxylpolyethoxylethanol; NPAS2, neuronal PAS domain protein 2; PBS, phosphate buffered saline; PER/Per, Period protein/gene; SCF, Skp1-Cul1-F-box-protein; SCN, suprachiasmatic nuclei; TS, thymidylate synthase; VEGF, vascular endothelial growth factor; β-TrCP, beta-transducin repeat containing protein


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