Tumor suppression by the mammalian Period genes.
The Period (Per) genes are key circadian rhythm regulators in mammals. Expression of the mouse Per (mPer) genes have diurnal pattern in the suprachiamstic nuclei and in peripheral tissues. Genetic ablation mPER1 and mPER2 function results in a complete loss of circadian rhythm control based on wheel running activity in mice. In addition, these animals also display apparent premature aging and significant increase in neoplastic and hyperplastic phenotypes. When challenged by gamma-radiation, mPer2 deficient mice response by rapid hair graying, are deficient in p53-mediated apoptosis in thymocytes and have robust tumor occurrences. Our studies have demonstrated that the circadian clock function is very important for cell cycle, DNA damage response and tumor suppression in vivo. Temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2 and Gadd45alpha is deregulated in mPer2 mutant mice. In addition, genetic studies have demonstrated that many key regulators of cell cycle and growth control are also important circadian clock regulators confirming the critical role of circadian function in organismal homeostasis. Recently studies of human breast and endometrial cancers revealed that the loss and deregulation of PERIOD proteins is common in the tumor cells.
Lee
Cheng Chi
CC
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX 77030, USA. cheng.c.lee@uth.tmc.edu
D000204:Activity Cycles; D000818:Animals; D001683:Biological Clocks / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002940:Circadian Rhythm / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D056950:Period Circadian Proteins; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D005136:Eye Proteins; D009687:Nuclear Proteins; C539022:PER1 protein, human; C421902:PER2 protein, human; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors