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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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Article Article has an altmetric score of 18

Targeted expression of a human pituitary tumor–derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis

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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 5

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Pituitary morphology of PRL–ptd-FGFR4 and PRL-FGFR4 transgenic mice. (a)...
Pituitary morphology of PRL–ptd-FGFR4 and PRL-FGFR4 transgenic mice. (a) The pituitary of an 11-month-old PRL–ptd-FGFR4 transgenic female mouse (left) is large, with nodular distortion; compare with nontransgenic female littermate (right). (b) The pituitary of an 11-month-old PRL–ptd-FGFR4 transgenic female mouse (left) is enlarged, with a tumor in the right lobe and a larger tumor replacing the left lobe. Normal pituitary of a nontransgenic female littermate (right). (c) Western blotting of mouse serum reveals higher levels of circulating PRL in transgenic mice (+) than in nontransgenic mice (–). The two left lanes are from males (M); the four right lanes are from females (F). Basal PRL is lower in the nontransgenic male than in the nontransgenic females. The degree of elevation in transgenic mice correlated with size of tumor. Albumen (Alb) control indicates protein loading (lower). (d) The pituitary tumor (T) of an 11-month-old PRL–ptd-FGFR4 transgenic female mouse invades the hypothalamus (H). (e) The pituitary of an 11-month-old PRL–ptd-FGFR4 transgenic male mouse contains a tumor composed of small cells with chromophobic cytoplasm and prominent nuclei. There is loss of acinar architecture and increased vascularity. (f) Tumor cells contain PRL in PRL–ptd-FGFR4 transgenic mice. (g) Tumor cells in a PRL–ptd-FGFR4 transgenic mouse contain variable amounts of cytoplasmic FGFR4, similar to that seen in human tumors (Figure 2b). (h) The pituitary of a 12-month-old mouse transgenic for PRL-FGFR4 exhibits normal architecture and distribution of the various pituitary cell types. (i) Wild-type FGFR4 in a 12-month-old PRL-FGFR4 transgenic mouse has a membrane-staining pattern (arrows), and is found in scattered cells that correspond to lactotrophs.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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