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

Hong S Yoon1, Amr M Ghaleb, Mandayam O Nandan

  • 1Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Oncogene
|April 5, 2005
PubMed

Insights

The transcription factor KLF4 prevents centrosome amplification after DNA damage. KLF4 suppresses cyclin E expression, a key regulator of centrosome duplication, thus maintaining genomic stability.

Area of Science:

  • Cell biology
  • Molecular oncology
  • DNA damage response

Background:

  • Centrosome duplication is tightly regulated during the cell cycle.
  • The tumor suppressor p53 is known to influence centrosome duplication.
  • DNA damage can disrupt normal cell cycle progression and lead to genomic instability.

Purpose of the Study:

  • To investigate the role of Krüppel-like factor 4 (KLF4) in preventing centrosome amplification following gamma-irradiation-induced DNA damage.
  • To elucidate the molecular mechanisms by which KLF4 regulates centrosome duplication in response to DNA damage.

Main Methods:

  • Utilized HCT116 colon cancer cell lines with wild-type (p53+/+) and p53-null (p53-/-) alleles.
  • Administered gamma-irradiation to induce DNA damage.
  • Employing conditional induction of exogenous KLF4 and KLF4 inhibition using shRNA.
  • Assessed centrosome numbers, KLF4 activation, cyclin E levels, and Cdk2 activity.
  • Performed cotransfection experiments to analyze KLF4's effect on cyclin E promoter activity.

Main Results:

  • HCT116 p53+/+ cells maintained stable centrosome numbers post-irradiation, while HCT116 p53-/- cells showed centrosome amplification.
  • KLF4 activation was dependent on p53; its absence in p53-/- cells correlated with amplification.
  • Exogenous KLF4 suppressed amplification in irradiated p53-/- cells, whereas KLF4 inhibition in p53+/+ cells induced amplification.
  • KLF4 deficiency led to increased cyclin E levels and Cdk2 activity, promoting centrosome amplification.
  • KLF4 overexpression repressed cyclin E promoter activity.

Conclusions:

  • KLF4 is essential and sufficient for preventing centrosome amplification after gamma-radiation-induced DNA damage.
  • KLF4 exerts its function by transcriptionally suppressing cyclin E expression.
  • This mechanism highlights KLF4's critical role in maintaining genomic stability following DNA damage.

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