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

Oncogene volume 24, pages 4017–4025 (2005)Cite this article

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.

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Abbreviations

BSA:

bovine serum albumin

Cdk2:

cyclin-dependent kinase 2

DPBS:

Dulbecco's phosphate-buffered saline

FBS:

fetal bovine serum

GKLF:

gut-enriched Krüppel-like factor

KLF4:

Krüppel-like factor 4

MEFs:

mouse embryonic fibroblasts

PBS:

phosphate-buffered saline

shRNA:

small hairpin RNA

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Acknowledgements

We thank Dr B Vogelstein for providing the HCT116 p53+/+ and HCT116 p53−/− cell line and Dr R Weinberg for providing the cyclin E luciferase reporter plasmid. This work was in part supported by grants from the National Institutes of Health (DK52230, DK64399, and CA84197). VWY is the recipient of a Georgia Cancer Coalition Distinguished Cancer Clinician Scientist award. WBD is a recipient of a Medical Scientist Training Program grant.

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Authors and Affiliations

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

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

  2. Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    Vincent W Yang

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  1. Hong S Yoon
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Correspondence to Vincent W Yang.

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Yoon, H., Ghaleb, A., Nandan, M. et al. Krüppel-like factor 4 prevents centrosome amplification following γ-irradiation-induced DNA damage. Oncogene 24, 4017–4025 (2005). https://doi.org/10.1038/sj.onc.1208576

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