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J. Biol. Chem., Vol. 279, Issue 50, 52141-52149, December 10, 2004

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Identification and Characterization of the IKK Promoter

POSITIVE AND NEGATIVE REGULATION BY ETS-1 AND p53, RESPECTIVELY^*

Lubing Gu, Ningxi Zhu, Harry W. Findley, William G. Woods, and Muxiang Zhou

From the Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322

IKK, a subunit of IkB kinase (IKK) complex, has an important role in the activation of nuclear factor-kB (NF-kB), a key regulator of normal and tumor cell proliferation, apoptosis, and response to chemotherapy. However, little is known about the transcriptional regulation of the IKK gene itself. The present study revealed that the transcriptional induction of the IKK gene is positively regulated by binding ETS-1, the protein product of the ETS-1 proto-oncogene. Furthermore, ETS-1 mediated activation of IKK is negatively regulated by p53 binding to ETS-1. By analyzing the genomic DNA sequence, we identified the putative IKK promoter sequence in the 5'-flanking untranslated region of the IKK gene. Transfection of EU-4, an acute lymphoblastic leukemia (ALL) cell line, with plasmids containing the IKK 5'-untranslated region sequence upstream of the luciferase reporter showed that this region possessed major promoter activity. Induction or enforced overexpression of p53 represses IKK mRNA and protein expression as well as IKK promoter activity. Deletion and mutation analyses as well as chromatin immunoprecipitation and electrophoretic mobility shift assay indicated that ETS-1 binds to the core IKK promoter and strongly induces its activity. Although p53 does not directly bind to the IKK promoter, it physically interacts with ETS-1 and specifically inhibits ETS-1-induced IKK promoter activity. These results suggest that the proximal 5'-flanking region of the IKK gene contains a functional promoter reciprocally regulated by p53 and ETS-1. Furthermore, loss of p53-mediated control over ETS-1-dependent transactivation of IKK may represent a novel pathway for the constitutive activation of NF-kB-mediated gene expression and therapy resistance in cancer.

Received for publication, July 14, 2004 , and in revised form, October 1, 2004.

^* This work was supported by National Institutes of Heath Grant R01 CA82323, Leukemia and Lymphoma Society Grant 6249-05, 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Division of Pediatric Hematology/Oncology/BMT, 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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