The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo

Cell. 2002 Oct 4;111(1):41-50. doi: 10.1016/s0092-8674(02)00961-3.

Abstract

The Period2 gene plays a key role in controlling circadian rhythm in mice. We report here that mice deficient in the mPer2 gene are cancer prone. After gamma radiation, these mice show a marked increase in tumor development and reduced apoptosis in thymocytes. The core circadian genes are induced by gamma radiation in wild-type mice but not in mPer2 mutant mice. Temporal expression of genes involved in cell cycle regulation and tumor suppression, such as Cyclin D1, Cyclin A, Mdm-2, and Gadd45alpha, is deregulated in mPer2 mutant mice. In particular, the transcription of c-myc is controlled directly by circadian regulators and is deregulated in the mPer2 mutant. Our studies suggest that the mPer2 gene functions in tumor suppression by regulating DNA damage-responsive pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Northern
  • Blotting, Western
  • Cell Cycle
  • Cell Cycle Proteins*
  • Cell Division
  • Cyclin A / genetics
  • Cyclin D1 / genetics
  • DNA Damage*
  • Dimerization
  • Flow Cytometry
  • Gamma Rays
  • Genetic Predisposition to Disease
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Neoplasms, Experimental / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology*
  • Period Circadian Proteins
  • Phenotype
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins c-myc / metabolism
  • Thymus Gland / cytology
  • Time Factors
  • Transcription Factors / metabolism
  • Transfection
  • Tumor Suppressor Protein p53 / genetics

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cyclin A
  • Gadd45a protein, mouse
  • Nerve Tissue Proteins
  • Npas2 protein, mouse
  • Nuclear Proteins
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Cyclin D1
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2