Fibroblast growth factor receptor 3 gene transcription is suppressed by cyclic adenosine 3',5'-monophosphate. Identification of a chondrocytic regulatory element
| Autor: | D G, McEwen, R P, Green, M C, Naski, D A, Towler, D M, Ornitz |
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| Rok vydání: | 1999 |
| Předmět: |
Transcription
Genetic Molecular Sequence Data 8-Bromo Cyclic Adenosine Monophosphate Regulatory Sequences Nucleic Acid Transfection Cell Line Mice 1-Methyl-3-isobutylxanthine Cyclic AMP Animals Humans Receptor Fibroblast Growth Factor Type 3 Growth Plate Cyclic AMP Response Element-Binding Protein Promoter Regions Genetic Receptor Parathyroid Hormone Type 1 Base Sequence Protein-Tyrosine Kinases Receptors Fibroblast Growth Factor Recombinant Proteins Kinetics Gene Expression Regulation Oligodeoxyribonucleotides Parathyroid Hormone Mutagenesis Site-Directed Receptors Parathyroid Hormone |
| Zdroj: | The Journal of biological chemistry. 274(43) |
| ISSN: | 0021-9258 |
| Popis: | Signaling through fibroblast growth factor receptors (FGFRs) is critical for the development and patterning of the vertebrate skeleton. Gain-of-function alleles of fgfr2 and fgfr3 have been linked to several dominant skeletal disorders in humans, while null mutations in fgfr3 result in the overgrowth of long bones in a mouse model system. Interestingly, the expression pattern of fgfr3 in growth plate chondrocytes overlaps that of the parathyroid hormone (PTH)-related peptide (PTHrP) receptor, a signaling molecule that also regulates endochondral ossification. The coincident expression of these two receptors suggests that their signaling pathways may also interact. To gain insight into the regulatory mechanism(s) that govern the expression of the fgfr3 gene in chondrocytes, we have identified a cell-specific transcriptional regulatory element (CSRh) by measuring the activity of various promoter fragments in FGFR3-expressing (CFK2) and nonexpressing (RCJ) chondrocyte-like cell lines. Furthermore, we demonstrate that activation of PTH/PTHrP receptors, either by stimulation with PTH or through the introduction of activating mutations, represses CSRh-mediated transcriptional activity. Finally, the transcriptional repression of the CSRh element was mimicked by treatment with forskolin, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine or by overexpression of the catalytic subunit of protein kinase A. Together, these data suggest that protein kinase A activity is a critical factor that regulates fgfr3 gene expression in the proliferative or prehypertrophic compartment of the epiphyseal growth plate. Furthermore, these results provide a possible link between PTHrP signaling and fgfr3 gene expression during the process of endochondral ossification. |
| Databáze: | OpenAIRE |
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