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J. Biol. Chem., Vol. 279, Issue 6, 5035-5041, February 6, 2004

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Requirement of Krüppel-like Factor 4 in Preventing Entry into Mitosis following DNA Damage^*

Hong S. Yoon and Vincent W. Yang¶

From the Division of Digestive Diseases, Department of Medicine, and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322

Previous studies indicate that Krüppel-like factor 4 (KLF4 or GKLF) controls the G₁/S cell cycle checkpoint upon DNA damage. We present evidence for an equally important role of KLF4 in maintaining the integrity of the G₂/M checkpoint following DNA damage. HCT116, a colon cancer cell line with wild type p53 alleles, underwent sustained G₂ arrest up to 4 days after -irradiation. In contrast, HCT116 cells null for p53 were able to enter mitosis following irradiation. Western blot analyses of irradiated HCT116 cells showed increased levels of p53, KLF4, and p21^WAF1/CIP1 and decreased levels of cyclin B1 when compared with unirradiated controls. In contrast, the levels of cyclin B1 increased in irradiated HCT116 p53-/- cells, in which KLF4 failed to increase due to the absence of p53. When KLF4 was inhibited by small interfering RNA, irradiated HCT116 cells exhibited increased mitotic indices and a rise in cyclin B1 levels. Conversely, irradiated HCT116 p53-/- cells that were infected with KLF4-expressing adenoviruses demonstrated a concurrent reduction in mitotic indices and cyclin B1 levels. In each case, Cdc2 kinase measurements showed an inverse correlation between Cdc2 kinase activities and KLF4 levels. Co-transfection experiments showed that KLF4 repressed the cyclin B1 promoter through a specific GC-rich element. Moreover, chromatin immunoprecipitation experiments demonstrated that both KLF4 and HDAC were associated with the cyclin B1 promoter in irradiated HCT116 cells. We conclude that KLF4 is essential in preventing mitotic entry following -irradiation and does so by inhibiting cyclin B1 expression.

Received for publication, July 15, 2003 , and in revised form, October 31, 2003.

^* This work was supported in part by National Institutes of Health Grants DK52230, DK64399, and CA84197. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Recipient of a Georgia Cancer Coalition Distinguished Cancer Clinician Scientist Award. To whom correspondence should be addressed: Division of Digestive Diseases, Dept. of Medicine, 201 Whitehead Research Bldg., 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-5638; Fax: 404-727-5767; E-mail: vyang{at}emory.edu.

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