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The Variant Hepatocyte Nuclear Factor 1 Activates the P1 Promoter of the Human -Folate Receptor Gene in Ovarian Carcinoma¹

Unit of Molecular Therapies, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy [A. T., F. M., M. M., S. S., S. M., E. G., S. C.], and Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [P. C. E.]

The folate receptor (FR) is a membrane glycoprotein that binds folates, and mediates their uptake and that of antifolate drugs. FR is absent on ovarian surface epithelium (OSE) but is detectable during early transforming events in this epithelium, with increasing expression levels in association with tumor progression. Analysis of transcriptional regulation of the FR gene have revealed two promoter regions, P1 and P4, flanking exons 1 and 4, respectively, and a requirement for three SP1 sites and an INR element for optimal P4 activity. Here, we focused on the P1 transcription regulation in ovarian carcinoma cells. RNase protection assay indicated that the 5'-untranslated region is heterogeneous because of different start sites and alternative splicing of exon 3. A core region of the P1 promoter was sufficient for maximal promoter activity in ovarian carcinoma cell lines but not in OSE cells or in FR-nonexpressing cell lines. Deletion and mutation analysis of this core promoter identified a cis-regulatory element at position +27 to +33 of the untranslated exon 1, which is responsible for maximum P1 activity. This element formed an abundant DNA-protein complex with nuclear proteins from ovarian cancer cells but not from other cell lines or OSE cells. Competition experiments and supershift assays demonstrated binding of the P1 cis-regulatory element by a transcription factor involved in embryonic development, the variant hepatocyte nuclear factor-1 (vHNF1). Analysis of RNA from various cell lines and surgical specimens confirmed that vHNF1 is expressed in ovarian carcinomas. Thus, vHNF1 regulates tissue-specific transcription in ovarian carcinoma.

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