The circadian clock and tumor suppression by mammalian period genes.

Period (Per) genes are key circadian rhythm regulators in mammals. Expression of mouse Per (mPer) genes has a diurnal pattern in the suprachiasmatic nucleus 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 a significant increase in neoplastic and hyperplastic phenotypes. When challenged by gamma radiation, mPer2-deficient mice respond by rapid hair graying, are deficient in p53-mediated apoptosis in thymocytes, and have robust tumor occurrences. Studies have demonstrated that the circadian clock function is very important for cell cycle, DNA damage response, and tumor suppression in vivo. The 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. 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.