Circadian gene mPer2 overexpression induces cancer cell apoptosis

Circadian rhythms, which are daily oscillations regulated by an endogenous clock,(1–3) enable organisms to adapt to daily environmental changes such as light, temperature and social communication, and serve to synchronize multiple molecular, biochemical, physiological and behavioral processes.(4–6) Recent studies suggest that the circadian system is not only required for proper growth control, but is also involved in the circadian regulation of cell proliferation and apoptosis.(7–9) It has been reported that 2–10% of all mammalian genes are clock-controlled.(4,5,10–12) Most of these show tissue- or organ-specific expression and are involved in organ function. Only a small set of clock-controlled genes are expressed in multiple organs. Among them are genes that encode key regulators of cell cycle progression.(10,11) Deregulation of the circadian clock may disturb the expression of clock-controlled genes and can have a profound influence on organ function. It is now documented that alterations in circadian rhythm can be associated with cancers in both animal and human tumors.(13,14) Up to now, at least eight core circadian clock genes have been identified in mammals and humans,(2,15) and the Period2 gene is regarded as an indispensable component of the circadian clock.(16) Gene targeting studies have demonstrated that the deletion of mPer2 induces arrhythmicity at both the behavioral and molecular levels.(17) Mice without mPER2 function have a transient rhythm with a shortened period length of 22 h. A majority of mutant mice lose the persistence of circadian rhythm when placed in free-running conditions.(18) The mice deficient in the mPer2 gene were cancer-prone. After γ radiation, these mice showed a marked increase in tumor development and reduced apoptosis in thymocytes. Temporal expression of the genes involved in cell cycle regulation and tumor suppression, such as Cyclin D1, Cyclin A, Mdm-2 and Gadd45, were reportedly altered in mPer2 mutant mice.(19) The relationship between mPer2 and cancer still lacks direct demonstration. In the present study, we transferred pcDNA3.1(+)-mPer2 into LLC cells, EMT6 cells and NIH 3T3 cells, assessed the effect of mPER2 overexpression on these cells and explored the possible signaling pathways leading to apoptotic cell death. Results show that overexpression of mPER2 may induce tumor cell apoptosis by the p53-mediated mitochondrial signaling pathway.