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

Author:

O’Shea Patrick J.12,Guigon Celine J.1,Williams Graham R.2,Cheng Sheue-yann1

Affiliation:

1. 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;

2. 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

Abstract

T3 is essential for normal skeletal development, acting mainly via the TRα1 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 TRα1 or TRβ, 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 TRβPV/PV littermate mice. T3 treatment increased Fgfr1 expression 2-fold in wild-type cells, but 8-fold in TRβPV/PV osteoblasts. The 4-fold increased T3 sensitivity of TRβPV/PV osteoblasts was associated with a markedly increased ratio of TRα1:TRβ1 expression that resulted from reduced TRβ1 expression in TRβPV/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.

Publisher

The Endocrine Society

Subject

Endocrinology

Reference45 articles.

1. Multiple mechanisms for regulation of the transcriptional activity of thyroid hormone receptors.;Cheng;Rev Endocr Metab Disord,2000

2. Capacity for cooperative binding of thyroid hormone (T3) receptor dimers defines wild type T3 response elements.;Brent;Mol Endocrinol,1992

3. Assembly of recombinant TFIID reveals differential coactivator requirements for distinct transcriptional activators.;Chen;Cell,1994

4. Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions.;Bassett;Mol Cell Endocrinol,2003

5. Physiological and molecular basis of thyroid hormone action.;Yen;Physiol Rev,2001

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