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      Transcriptional regulation by transforming growth factor beta of the expression of retinoic acid and retinoid X receptor genes in osteoblastic cells is mediated through AP-1.

      The Journal of Biological Chemistry
      1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, pharmacology, Animals, Binding, Competitive, Blotting, Northern, Cell Line, Curcumin, DNA-Binding Proteins, genetics, Electrophoresis, Polyacrylamide Gel, Enzyme Inhibitors, Gene Expression Regulation, drug effects, Humans, Mice, Nuclear Proteins, Osteoblasts, metabolism, Receptors, Retinoic Acid, Retinoid X Receptors, Transcription Factor AP-1, antagonists & inhibitors, Transcription Factors, Transcription, Genetic, Transforming Growth Factor beta

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          Abstract

          We now report that transforming growth factor beta1 (TGF-beta1), a potent regulatory cytokine of bone remodeling, is a powerful stimulator for gene expression of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in osteoblastic MC3T3-E1 cells. TGF-beta1 transcriptionally stimulated the expression of RARalpha, RARgamma, and RXRalpha genes, but did not do so for RARbeta, RXRbeta, and RXRgamma genes. We also observed that AP-1, a transcriptional factor, plays an important role in the signal pathway for expression of RARalpha, RARgamma, and RXRalpha genes stimulated by TGF-beta1 because stimulation of the expression of these genes in the cytokine-treated cells was markedly inhibited by a mixture of antisense c-fos and c-jun. A gel mobility shift assay demonstrated that TGF-beta1 is able to increase, in a dose-dependent manner, the binding of nuclear proteins to direct repeat 5, a consensus sequence with high affinity for RAR-RXR heterodimers. The mobility shift assay, using specific antibody for each receptor, showed that direct repeat 5-binding proteins may be RAR and RXR isoforms. The stimulated binding to direct repeat 5 was inhibited strongly by H-7, an inhibitor of serine/threonine kinase, and by curcumin, an inhibitor of AP-1. The present study suggests a novel pathway for TGF-beta1 action in osteoblastic cells via stimulation of RAR-RXR transcriptional activity in a ligand-dependent fashion.

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