Tumor Suppression by the Mammalian Period Genes
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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 γ-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 Gadd45α 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.
KeywordsCircadian rhythm Mammal Period gene Tumor suppression
I would like to thank Dr. J. Lever for comments on this manuscript. This work is supported in part by funding from NIH.
- 9.Shiromani PJ, Xu M, Winston EM, Shiromani SN, Gerashchenko D, Weaver DR (2004) Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes. Am J Physiol Regul Integr Comp Physiol 287:47–57Google Scholar
- 17.Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG (2005) Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis. 2005 Mar 24; [Epub ahead of print]Google Scholar