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J. Biol. Chem., Vol. 281, Issue 41, 30419-30430, October 13, 2006

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Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor^*

Alejandro López-Soto¹, Adolfo Quiñones-Lombraña, Rubén López-Arbesú, Carlos López-Larrea, and Segundo González²

From the Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo and the Unidad de Histocompatibilidad y Transplantes, Hospital Universitario Central de Asturias, Oviedo, Spain

Tumor cells expressing ligands of the NKG2D receptor stimulate anti-tumor immunity mediated by natural killer and T cells. In humans, NKG2D ligands (NKG2DL) are encoded by MIC and ULBP proteins. NKG2DL exhibit highly restricted expression in healthy tissues but are widely expressed in tumors. However, regulation of each NKG2DL differs substantially in different cancer cells. In this study, we characterized the mechanisms that regulate the expression of ULBP1. We show that the transcription of ULBP1 strictly depends on the binding of Sp1 and Sp3 to a CRE(1) site located in the ULBP1 minimal promoter. The mutation or deletion of this Sp1/Sp3 binding site abolished the transcription of ULBP1. It also diminished the transactivation of ULBP1 promoter by Sp3 overexpression, but not by Sp1, indicating that Sp3 is the main transcription factor that regulates ULBP1 through the CRE(1) site. Experiments in SL2 cells showed that the ULBP1 promoter was inactive in the absence of the Sp proteins and indicate that Sp3 is the essential activator of ULBP1 transcription, because the overexpression of Sp3 up-regulated its promoter activity >500-fold. Additionally, we demonstrated that AP-2 repressed the expression of ULBP1 in HeLa cells by interfering with the binding of Sp3 and Sp1 to the ULBP1 promoter. These data indicate that Sp1, Sp3, and AP-2 may play an important role in the immunosurveillance against cancer. Finally, the definition of ULBP1 regulation may have implications for development of new therapeutic strategies against cancer cells.

Received for publication, May 19, 2006 , and in revised form, August 3, 2006.

^* This work was supported in part by Grant 03/0067 from the Fondo de Investigaciones Sanitarias from the Spanish Ministerio de Sanidad y Consumo. 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 Recipient of a grant from the Fondo de Investigaciones Sanitarias.

² To whom correspondence should be addressed: Tel.: 34-985-106-264; Fax: 34-985-103-606; E-mail: segundog{at}uniovi.es.

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