Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage

Oncogene. 2005 Jun 9;24(25):4017-25. doi: 10.1038/sj.onc.1208576.

Abstract

Centrosome duplication is a carefully controlled process in the cell cycle. Previous studies indicate that the tumor suppressor, p53, regulates centrosome duplication. Here, we present evidence for the involvement of the mammalian Krüppel-like transcription factor, KLF4, in preventing centrosome amplification following DNA damage caused by gamma-irradiation. The colon cancer cell line HCT116, which contains wild-type p53 alleles (HCT116 p53+/+), displayed stable centrosome numbers following gamma-irradiation. In contrast, HCT116 cells null for the p53 alleles (HCT116 p53-/-) exhibited centrosome amplification after irradiation. In the latter cell line, KLF4 was not activated following gamma-irradiation due to the absence of p53. However, centrosome amplification could be suppressed in irradiated HCT116 p53-/- cells by conditional induction of exogenous KLF4. Conversely, in a HCT116 p53+/+ cell line stably transfected with small hairpin RNA (shRNA) designed to specifically inhibit KLF4, gamma-irradiation induced centrosome amplification. In these cells, the inability of KLF4 to become activated in response to DNA damage was directly associated with an increase in cyclin E level and Cdk2 activity, both essential for regulating centrosome duplication. Cotransfection experiments showed that KLF4 overexpression suppressed the promoter activity of the cyclin E gene. The results of this study demonstrated that KLF4 is both necessary and sufficient in preventing centrosome amplification following gamma-radiation-induced DNA damage and does so by transcriptionally suppressing cyclin E expression.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Centrosome / physiology*
  • Colonic Neoplasms
  • Cyclin E / genetics
  • DNA Damage / radiation effects*
  • DNA-Binding Proteins / physiology*
  • Gamma Rays*
  • Gene Deletion
  • Genes, p53
  • Humans
  • Kruppel-Like Transcription Factors
  • RNA / genetics
  • Transcription Factors / physiology*
  • Transfection

Substances

  • Cyclin E
  • DNA-Binding Proteins
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Transcription Factors
  • RNA