Journal
ONCOGENE
Volume 24, Issue 25, Pages 4017-4025Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208576
Keywords
cell cycle; GKLF; p53; cyclin E; Cdk2; small hairpin RNA (shRNA)
Funding
- NCI NIH HHS [CA84197, R01 CA084197] Funding Source: Medline
- NIDDK NIH HHS [DK64399, DK52230, R24 DK064399, R01 DK052230] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008169] Funding Source: Medline
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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 Kruppel-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.
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