Targeted expression of a human pituitary tumor–derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis
Shereen Ezzat, … , Gillian E. Wu, Sylvia L. Asa
Shereen Ezzat, … , Gillian E. Wu, Sylvia L. Asa
Published January 1, 2002
Citation Information: J Clin Invest. 2002;109(1):69-78. https://doi.org/10.1172/JCI14036.
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Targeted expression of a human pituitary tumor–derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis

Abstract

It is estimated that up to one in five individuals develop pituitary gland tumors. Despite the common occurrence of these tumors, the pathogenetic mechanisms underlying their development remain largely unknown. We report the identification of a novel pituitary tumor–derived, N-terminally truncated isoform of FGF receptor-4 (ptd-FGFR4). The corresponding mRNA results from alternative transcription initiation and encodes a polypeptide that lacks a signal peptide and the first two extracellular Ig-like domains. ptd-FGFR4 has a distinctive cytoplasmic residence, is constitutively phosphorylated, and is transforming in vitro and in vivo. Here we show that targeted expression of ptd-FGFR4, but not FGFR4, results in pituitary tumors that morphologically recapitulate the human disease.

Authors

Shereen Ezzat, Lei Zheng, Xian-Feng Zhu, Gillian E. Wu, Sylvia L. Asa

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Figure 1

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FGFR4 gene and protein structure, and RNA analysis. (a) The gene (top) c...
FGFR4 gene and protein structure, and RNA analysis. (a) The gene (top) contains 18 exons. The protein (bottom) is a transmembrane tyrosine kinase with three extracellular Ig-like loops. Exon 1 is untranslated. Exon 2 encodes signal peptide (SP). Exon 3 encodes first Ig-like domain (I1). Exon 4 encodes acid box (AB). Exons 5 and 6 encode second Ig-like domain (I2). Exons 7 and 8 encode third Ig-like domain (I3). Exon 9 encodes trans-membrane domain (TM). Exons 10–12 and 14–17 encode split kinase (K1 and K2). (b) RT-PCR of RNA from human pituitary tumors and normal pituitaries (N), identified an 818-bp product (exons 7–12) of FGFR4 in five of seven tumors, but not in normals. RNA integrity is indicated by RT-PCR for PGK-1 (bottom). Negative controls omitted reverse transcriptase (–). (c) Although the predicted 1,500-bp mRNA encoding full-length FGFR4 was present in MCF-7 breast cancer cells (+), it is undetectable in normal pituitary and tumors. PCR on the same samples, using corresponding primers in signal peptide and kinase domains of FGFR1, resulted in products of the predicted 1,700-bp size (bottom). (d) Northern blot analysis of hFGFR4 expression. A 2.3 kb band is identified in RNA from MCF-7 cells (+). Normal pituitary (N) is negative; two pituitary tumors (T1 and T2) contain smaller bands of approximately 1.7 kb. Hybridization with PGK-1 cDNA identifies a 1.8-kb species (bottom). (e) RACE. Arrow in the exon 5/6 sequence indicates the farthest 5′ transcription initiation site in 5′ RACE-generated products from pituitary tumors. The putative in-frame ATG translational start site is indicated in bold italics. (Sequence 492–782, following GenBank FGFR4 cDNA sequence accession no. X57205).