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Regulation of Fibroblast Growth Factor Receptor-1 (Fgfr1) by Thyroid Hormone: Identification of a Thyroid Hormone Response Element in the Murine Fgfr1 Promoter

Gene Regulation Section (P.J.O, C.J.G., S.C.), Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264; and Molecular Endocrinology Group (P.J.O., G.R.W.), Division of Medicine and Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom

Address all correspondence and requests for reprints to: Dr. Sheue-yann Cheng, Chief, Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264. E-mail: chengs{at}mail.nih.gov.

T₃ is essential for normal skeletal development, acting mainly via the TR1 nuclear receptor. Nevertheless, the mechanisms of T₃ action in bone are poorly defined. Fibroblast growth factor receptor-1 (FGFR1) is also essential for bone formation. Fgfr1 expression and activity are positively regulated by T₃ in osteoblasts, and in mice that harbor a dominant negative PV mutation targeted to TR1 or TRß, Fgfr1 expression is sensitive to skeletal thyroid status. To investigate mechanisms underlying T₃ regulation of FGFR1, we obtained primary calvarial osteoblasts from wild-type and TRß^PV/PV littermate mice. T₃ treatment increased Fgfr1 expression 2-fold in wild-type cells, but 8-fold in TRß^PV/PV osteoblasts. The 4-fold increased T₃ sensitivity of TRß^PV/PV osteoblasts was associated with a markedly increased ratio of TR1:TRß1 expression that resulted from reduced TRß1 expression in TRß^PV/PV osteoblasts compared with wild-type. Bioinformatics and gel shift studies, and mutational analysis, identified a specific TR binding site 279–264 nucleotides upstream of the murine Fgfr1 promoter transcription start site. Transient transfection analysis of a series of Fgfr1 promoter 5'-deletion constructs, of a mutant reporter construct, and a series of heterologous promoter constructs, confirmed that this region of the promoter mediates a TR-dependent transcriptional response to T₃. Thus, in addition to indirect regulation of FGFR1 expression by T₃ reported previously, T₃ also activates the Fgfr1 promoter directly via a thyroid hormone response element located at positions –279/–264.

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