Period2 downregulation inhibits glioma cell apoptosis by activating the MDM2-TP53 pathway

Oncotarget. 2016 May 10;7(19):27350-62. doi: 10.18632/oncotarget.8439.

Abstract

The Period2 (Per2) gene is an essential component of the mammalian circadian clock and is strongly linked to glioma occurrence and its response to radiotherapy. Here, we examined the role of Per2 in the response to X-ray-induced DNA damage in U343 glioma cells and in a mouse cancer model. Following low dose X-ray irradiation, we observed that lowering Per2 expression using RNAi reduces DNA damage and cell death in U343 cells and glioma tissue. Additionally, Per2 was associated with increased TP53 activity and was involved in the DNA damage during TP53-mediated apoptosis. These findings suggest that Per2, a core circadian gene, is not only a tumor suppressor gene but can also be regarded as an upstream regulator of TP53. It thus appears that Per2 is an important inhibitor of tumor growth that acts by increasing TP53 expression, DNA damage repair, and apoptosis.

Keywords: TP53; U343 cells; X-ray; glioma; period2.

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Cell Line, Tumor
  • DNA Damage
  • DNA Repair / genetics
  • Down-Regulation*
  • Glioma / genetics*
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Period Circadian Proteins / genetics*
  • Period Circadian Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA Interference
  • Signal Transduction / genetics
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • X-Rays

Substances

  • PER2 protein, human
  • Period Circadian Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2