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

Hong S. Yoon, Amr M. Ghaleb, Mandayam O. Nandan, Irfan M. Hisamuddin, William Brian Dalton, Vincent W. Yang

Research output: Contribution to journalArticlepeer-review

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 γ-irradiation. The colon cancer cell line HCT116, which contains wild-type p53 alleles (HCT116 p53 +/+), displayed stable centrosome numbers following γ-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 γ-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, γ-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 γ-radiation- induced DNA damage and does so by transcriptionally suppressing cyclin E expression.

Original languageEnglish (US)
Pages (from-to)4017-4025
Number of pages9
JournalOncogene
Volume24
Issue number25
DOIs
StatePublished - Jun 9 2005
Externally publishedYes

Keywords

  • Cdk2
  • Cell cycle
  • Cyclin E
  • GKLF
  • Small hairpin RNA (shRNA)
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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