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J. Biol. Chem., Vol. 281, Issue 1, 51-58, January 6, 2006

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Regulation of KiSS-1 Metastasis Suppressor Gene Expression in Breast Cancer Cells by Direct Interaction of Transcription Factors Activator Protein-2 and Specificity Protein-1^*

Dianne C. Mitchell, Maen Abdelrahim, Jinsheng Weng, Lewis J. Stafford, Stephen Safe, Menashe Bar-Eli, and Mingyao Liu1

From the Institute of Biosciences and Technology, Department of Medical Biochemistry and Genetics, Texas A&M University System Health Science Center and the Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030

KiSS-1 has been shown to function as a tumor metastasis suppressor gene and reduce the number of metastases in different cancers. The expression of KiSS-1 or KiSS1, like other tumor suppressor, is commonly reduced or completely ablated in a variety of cancers via an unknown mechanism. Here we show that the loss of KiSS-1 expression in highly metastatic breast cancer cell lines correlates directly with the expression levels of two transcription factors, activator protein-2 (AP-2) and specificity protein 1 (Sp1), which synergistically activate the transcriptional regulation of KiSS-1 in breast cancer cells. Although the KiSS-1 promoter contains multiple AP-2 binding elements, AP-2-mediated regulation occurs indirectly through Sp1 sites, as determined by deletion and mutation analysis. Overexpression of AP-2 into highly metastatic breast cell lines did not alter KiSS-1 promoter-driven luciferase gene activity. However, co-transfection of AP-2 wild-type or the dominant negative form of AP-2 lacking its C-terminal DNA-binding domain, AP-2B, together with Sp1, increased KiSS-1 promoter activity dramatically, suggesting that AP-2 regulation of KiSS-1 transcription does not require direct binding to the KiSS-1 promoter. Furthermore, we demonstrated that AP-2 directly interacted with Sp1 to form transcription complexes at two tandem Sp1-binding sites of the promoter to activate KiSS-1 transcription. Together, our results indicate that AP-2 and Sp1 are strong transcriptional regulators of KiSS-1 and that loss or decreased expression of AP-2 in breast cancer may account for the loss of tumor metastasis suppressor KiSS-1 expression and thus increased cancer metastasis.

Received for publication, June 8, 2005 , and in revised form, October 21, 2005.

^* This work was supported by Predoctoral Traineeship Award BC044338 from the Department of Defense Breast Cancer Program (to D. M.) and by National Institutes of Health Grants 5R01HL064792 and 1R01CA106479 (to M. L.). 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 To whom correspondence should be addressed: Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030. Tel.: 713-677-7505; Fax: 713-677-7512; E-mail: mliu{at}ibt.tamhsc.edu.

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