title: The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis.
abstract: Circadian oscillation and cell cycle progression are the two most essential rhythmic events present in almost all organisms. Circadian rhythms keep track of time and provide temporal regulation with a period of about 24 h. The cell cycle is optimized for growth and division, but not for time keeping. Circadian gated cell divisions are observed in nearly all organisms. However, the implications of this coupling to the physiology of mammals are unknown. A mutation (S662G) in the clock protein PERIOD2 (PER2) is responsible for familial advanced sleep phase syndrome in which sleep onset occurs in the early evening and wakefulness occurs in the early morning. Here, we provide evidence that the PER2(S662) mutation leads to enhanced resistance to X-ray-induced apoptosis and increased E1A- and RAS-mediated oncogenic transformation. Accordingly, the PER2(S662) mutation affects tumorigenesis in cancer-sensitized p53(R172H/+) mice. Finally, analyzing the clock-controlled cell cycle genes p21, c-Myc, Cyclin D1 and p27, we found that the relative phases between p21 and Cyclin D expression profiles have been changed significantly in these Per2 allele mutant mouse embryonic fibroblasts. This key role of the Per2-mediated phase alteration of p21 provides what we believe to be a novel mechanism in understanding cell cycle progression, its plasticity and its resistance to interference.
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Gu
authors.forename: L
authors.initials: L
authors.lastname: Xing
authors.forename: G
authors.initials: G
authors.lastname: Shi
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: Z
authors.initials: Z
authors.lastname: Qu
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002940:Circadian Rhythm; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D020178:Sleep Disorders, Circadian Rhythm / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins