The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells.

The Per1 gene is a core clock factor that plays an essential role in generating circadian rhythms. Recent data reveal that major biological pathways, including those critical to cell division, are under circadian control. We report here that Per1 provides an important link between the circadian system and the cell cycle system. Overexpression of Per1 sensitized human cancer cells to DNA damage-induced apoptosis; in contrast, inhibition of Per1 in similarly treated cells blunted apoptosis. The apoptotic phenotype was associated with altered expression of key cell cycle regulators. In addition, Per1 interacted with the checkpoint proteins ATM and Chk2. Ectopic expression of Per1 in human cancer cell lines led to significant growth reduction. Finally, Per1 levels were reduced in human cancer patient samples. Our results highlight the importance of circadian regulation to fundamental cellular functions and support the hypothesis that disruption of core clock genes may lead to cancer development.

[1]  M. Eilers,et al.  Transcriptional regulation and transformation by Myc proteins , 2005, Nature Reviews Molecular Cell Biology.

[2]  K. Kinzler,et al.  Requirement for p53 and p21 to sustain G2 arrest after DNA damage. , 1998, Science.

[3]  Ming-Feng Hou,et al.  Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. , 2005, Carcinogenesis.

[4]  Aziz Sancar,et al.  Coupling of Human Circadian and Cell Cycles by the Timeless Protein , 2005, Molecular and Cellular Biology.

[5]  Huichen Wang,et al.  DNA damage checkpoint control in cells exposed to ionizing radiation , 2003, Oncogene.

[6]  Stefano Iacobelli,et al.  Effects of light and food schedules on liver and tumor molecular clocks in mice. , 2005, Journal of the National Cancer Institute.

[7]  J. Takahashi,et al.  Mammalian circadian biology: elucidating genome-wide levels of temporal organization. , 2004, Annual review of genomics and human genetics.

[8]  F. Tamanini,et al.  Dimerization and nuclear entry of mPER proteins in mammalian cells. , 2000, Genes & development.

[9]  A. Sancar,et al.  Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. , 2004, Annual review of biochemistry.

[10]  S. Reppert,et al.  Coordination of circadian timing in mammals , 2002, Nature.

[11]  Stella Pelengaris,et al.  c-MYC: more than just a matter of life and death , 2002, Nature Reviews Cancer.

[12]  W. Hofmann,et al.  Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. , 2005, Blood.

[13]  J. Massagué,et al.  Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. , 2002, Nature.

[14]  C. Prives,et al.  Checkpoint Kinase 2 (Chk2) Monomers or Dimers Phosphorylate Cdc25C after DNA Damage Regardless of Threonine 68 Phosphorylation* , 2002, The Journal of Biological Chemistry.

[15]  H. A. Rogoff,et al.  Dual induction of apoptosis and senescence in cancer cells by Chk2 activation: checkpoint activation as a strategy against cancer. , 2005, Cancer research.

[16]  Paolo Sassone-Corsi,et al.  A Web of Circadian Pacemakers , 2002, Cell.

[17]  Francine Laden,et al.  Night-shift work and risk of colorectal cancer in the nurses' health study. , 2003, Journal of the National Cancer Institute.

[18]  松尾 拓哉.  Control mechanism of the circadian clock for timing of cell division in vivo , 2004 .

[19]  A. B. Reddy,et al.  Circadian clocks: neural and peripheral pacemakers that impact upon the cell division cycle. , 2005, Mutation research.

[20]  Peng Huang,et al.  The Circadian Gene Period2 Plays an Important Role in Tumor Suppression and DNA Damage Response In Vivo , 2002, Cell.

[21]  Kai-Florian Storch,et al.  Extensive and divergent circadian gene expression in liver and heart , 2002, Nature.

[22]  James Lyons-Weiler,et al.  Molecular overlap of fly circadian rhythms and human pancreatic cancer. , 2006, Cancer letters.

[23]  B. H. Miller,et al.  Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock , 2002, Cell.

[24]  Cheng Chi Lee.  The circadian clock and tumor suppression by mammalian period genes. , 2005, Methods in enzymology.

[25]  A. Schäffer,et al.  Atm haploinsufficiency results in increased sensitivity to sublethal doses of ionizing radiation in mice , 1999, Nature Genetics.

[26]  J. Mitchison.  Cell Biology , 1964, Nature.

[27]  J. Hansen,et al.  Light at night, shiftwork, and breast cancer risk. , 2001, Journal of the National Cancer Institute.

[28]  K Kume,et al.  Interacting molecular loops in the mammalian circadian clock. , 2000, Science.

[29]  J L Cleveland,et al.  Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. , 1998, Genes & development.

[30]  Jan-Gowth Chang,et al.  Abnormal expression of period 1 (PER1) in endometrial carcinoma , 2005, The Journal of pathology.

[31]  John M. Sedivy,et al.  c-Myc Regulates Cyclin D-Cdk4 and -Cdk6 Activity but Affects Cell Cycle Progression at Multiple Independent Points , 1999, Molecular and Cellular Biology.

[32]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[33]  Jiri Bartek,et al.  Cell-cycle checkpoints and cancer , 2004, Nature.

[34]  Robert T Abraham,et al.  Guiding ATM to Broken DNA , 2005, Science.

[35]  G. Stark,et al.  Analyzing the G2/M checkpoint. , 2004, Methods in molecular biology.

[36]  Y. Shiloh.  ATM and related protein kinases: safeguarding genome integrity , 2003, Nature Reviews Cancer.