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J. Biol. Chem., Vol. 281, Issue 21, 14711-14718, May 26, 2006

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KLF5 Interacts with p53 in Regulating Survivin Expression in Acute Lymphoblastic Leukemia^*

Ningxi Zhu¹, Lubing Gu¹, Harry W. Findley, Ceshi Chen, Jin-Tang Dong, Lily Yang^¶, and Muxiang Zhou²

From the The Division of Pediatric Hematology/Oncology, Winship Cancer Institute and Department of Hematology/Oncology, ^¶Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30322

The Kruppel-like factor 5 (KLF5) is a transcription factor that regulates cellular signaling involved in cell proliferation and oncogenesis. Here, we report that KLF5 interacts with tumor suppressor p53 in regulating the expression of the inhibitor-of-apoptosis protein survivin, which may play a role in pathological process of cancer. The core promoter region of survivin contains multiple GT-boxes that have been characterized as KLF5 response elements. Deletion and mutation analyses as well as chromatin immunoprecipitation and electronic mobility shift assay indicated that KLF5 binds to the core survivin promoter and strongly induces its activity. Furthermore, we demonstrated that KLF5 protein is able to bind to p53 and abrogate the p53-regulated repression of survivin. Transfection of KLF5 into a KLF5-negative acute lymphoblastic leukemia cell line EU-8 enhanced survivin expression, and conversely, silencing of KLF5 by small interfering RNA in a KLF5-overexpressing acute lymphoblastic leukemia cell line EU-4 down-regulated survivin expression. The KLF5 small interfering RNA-mediated down-regulation of survivin sensitized EU-4 cells to apoptosis induced by chemotherapeutic drug doxorubicin. These findings identify a novel regulatory pathway for the expression of survivin under the control of KLF5 and p53. Deregulation of this pathway may result in overexpression of survivin in cancer, thus contributing to drug resistance.

Received for publication, December 27, 2005 , and in revised form, March 30, 2006.

^* This work was supported by National Institutes of Health Grant R01 CA82323, The Leukemia and Lymphoma Society Grant 6249-05, and by the Children's Leukemia Research Association Inc. and CURE Childhood Cancer Inc. 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Pediatric Hematology/Oncology, Emory University School of Medicine, 2015 Uppergate Dr., Atlanta, GA 30322. Tel.: 404-727-1426; Fax: 404-727-4455; E-mail: mzhou{at}emory.edu.

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