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Negative Functional Interaction of Retinoic Acid and TGF-β Signaling Mediated by TG-interacting Factor During Chondrogenesis

Negative Functional Interaction of Retinoic Acid and TGF-β Signaling Mediated by TG-interacting Factor During Chondrogenesis,10.1159/000204104,Cellula

Negative Functional Interaction of Retinoic Acid and TGF-β Signaling Mediated by TG-interacting Factor During Chondrogenesis   (Citations: 2)
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We previously showed that atRA (all-trans Retinoic Acid, atRA) inhibites chondrogenesis by downregulation of TGF-β/Smad signaling. However, the molecular link between RA and TGF-β signaling is unknown. Using a mouse embryo palate mesenchyme micomass cultures (MMCs) system, we explored interactions of RA and TGF-β signaling during chondrogenesis. We found that atRA suppressed chondrogenesis and Smad2/3 phosphorylation regardless of the presence of TGF-β3. Functional assays indicated that TGF-β3 treatment or co-transfection of expressing Smad2/3 vectors suppressed atRA-induced RARE-tk-Luc activity. Conversely, atRA or RAR-overexpression repressed TGF-β3-induced transactivation of the TGF-β-responsive reporter, p3TP-Lux. ChIP assay revealed the binding of the Smad transcriptional co-repressor TGIF (TG-interacting factor, TGIF) to RARβ promoter in control MMCs, but this association was decreased by the addition of RA and increased by TGF-β3, respectively. Further examinations revealed that TGIF exerted a pivotal role in regulating crosstalk of RA and TGF-β signaling, since siRNA knockdown of TGIF partially abolished the ability of atRA to suppress TGF-β3-induced chondrogenesis, whereas forced expression of TGIF blocked the ability of TGF-β3 to relieve atRA-mediated the suppression of chondrogenesis. Furthermore, we demonstrated that the effects of atRA on TGF-β-dependent gene activation and of TGF-β on RA-dependent gene activation are mediated by TGIF with siRNA to downregulate TGIF. Collectively, these findings indicated a negative functional interplay of RA and TGF-β signaling mediated by TGIF to modulate chondrogenesis in MMCs.
Journal: Cellular Physiology and Biochemistry - CELL PHYSIOL BIOCHEM , vol. 23, no. 1-3, pp. 157-164, 2009
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