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

• Published in: Oncogene Vol. 24; no. 25; pp. 4017 - 4025
• Main Authors: Yoon, H S, Ghaleb, A M, Nandan, MO, Hisamuddin, I M, Dalton, W B, Yang, V W
• Format: Journal Article
• Language: English
• Published: 09.06.2005
• DOI: 10.1038/sj.onc.1208576
• ISSN: 0950-9232

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 Krueppel-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.