Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor
| Autor: | Adolfo Quiñones-Lombraña, Carlos López-Larrea, Ruben Lopez-Arbesu, Alejandro López-Soto, Segundo Gonzalez |
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| Rok vydání: | 2006 |
| Předmět: |
Molecular Sequence Data
Response element Biology GPI-Linked Proteins Ligands Biochemistry Transactivation Transcription (biology) Transcriptional regulation Humans Receptors Immunologic Binding site Promoter Regions Genetic Molecular Biology Transcription factor Genes Dominant Binding Sites Base Sequence Activator (genetics) Histocompatibility Antigens Class I Intracellular Signaling Peptides and Proteins Membrane Proteins Cell Biology Molecular biology Protein Structure Tertiary Gene Expression Regulation Neoplastic Sp3 Transcription Factor NK Cell Lectin-Like Receptor Subfamily K Cancer cell Receptors Natural Killer Cell Carrier Proteins HeLa Cells Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 281:30419-30430 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m604868200 |
| Popis: | 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 activity500-fold. Additionally, we demonstrated that AP-2alpha 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-2alpha 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. |
| Databáze: | OpenAIRE |
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