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J. Biol. Chem., Vol. 278, Issue 22, 19597-19602, May 30, 2003

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Pituitary Tumor AP-2 Recognizes a Cryptic Promoter in Intron 4 of Fibroblast Growth Factor Receptor 4^*

ShunJiang Yu , Sylvia L. Asa , Ronald J. Weigel ¶ and Shereen Ezzat  ||

From the Department of Medicine, Mount Sinai Hospital and the Department of Pathology, University Health Network, Freeman Centre for Endocrine Oncology and Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada and the ^¶Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Fibroblast growth factor receptors (FGFRs) have been implicated in a multitude of proliferative functions, and FGFR4 is expressed differentially in normal and neoplastic pituitary. Human pituitary tumors express a truncated FGFR4 isoform (ptd-FGFR4) for which transcription is initiated from a downstream alternative site. Analysis of FGFR4 intronic sequences predicted a possible promoter within intron 4 (In4) including a classic TATA box with a possible transcriptional start site in intron 5. We show here that the human In4 sequence can direct luciferase reporter activity in transfected pituitary GH4 cells. Four overlapping fragments (A1, A2, B1, and B2) of this intron were examined by electromobility shift assay using nuclear extracts from rat pituitary tumors. Of these, fragment B2 formed complexes with nuclear rat pituitary GH4 extracts that were competed specifically by wild type but not mutant oligonucleotides for the neural crest cell lineage-derived activating transcription factor AP-2. Conversely, an AP-2 consensus sequence probe was competed by the In4 B2 oligonucleotide but not by other fragments of the same intron. The In4 B2 complex was competed partially by NFB, supershifted by an AP-2-specific antibody, and co-migrated with the same probe incubated with recombinant AP-2 protein. We also examined the ability of primary human pituitary tumor extracts to interact with the In4 B2 fragment. Pituitary tumor-In4 B2 complexes were competed specifically by wild type AP-2 but not mutant AP-2 oligonucleotides. Western blotting revealed higher levels of AP-2 expression in primary human pituitary tumors than in nontumorous tissue. Mutagenesis of the putative AP-2 binding site in In4 B2 resulted in a marked loss of promoter activity in a luciferase assay. AP-2 transfection in the presence of the histone deacetylase inhibitor trichostatin-A resulted in enhanced expression of endogenous ptd-FGFR4. These data indicate that a cryptic promoter within intron 4 binds AP-2. AP-2 and chromatin changes may contribute to the utilization of an alternative transcription start site leading to the genesis of the tumorigenic ptd-FGFR4 isoform.

Received for publication, December 6, 2002 , and in revised form, January 28, 2003.

^* This work was supported by Canadian Institutes of Health Research Grant MT-14404 (to S. E. and S. L. A.) and by Toronto Medical Laboratories. 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.

^|| To whom correspondence should be addressed: University of Toronto-Mount Sinai Hospital, 600 University Ave., #437, Toronto, Ontario M5G 1X5, Canada. Tel.: 416-586-8505; Fax: 416-586-8834; E-mail: sezzat{at}mtsinai.on.ca.

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