کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2052413 | 1074230 | 2005 | 8 صفحه PDF | دانلود رایگان |
The transforming growth factor beta (TGFβ) and Wnt signaling pathways play central roles regulating embryogenesis and maintaining adult tissue homeostasis. TGFβ mediates its cellular effects through types I and II cell surface receptors coupled to the nucleocytoplasmic Smad proteins. Wnt signals via binding to a cell surface receptor, Frizzled, which in turn activates intracellular Dishevelled, ultimately leading to stabilization and nuclear translocation of β-catenin. Previous studies have demonstrated several points of cross-talk between the TGFβ and Wnt signaling pathways. In yeast two-hybrid and GST-pull down assays, Dishevelled-1 and Smad 3 have been shown to physically interact through the C-terminal one-half of Dishevelled-1 and the MH2 domain of Smad 3. The current study demonstrates that co-treatment of murine embryonic maxillary mesenchyme (MEMM) cells with Wnt-3a and TGFβ leads to enhanced reporter activity from TOPflash, a Wnt-responsive reporter plasmid. Transcriptional cooperation between TGFβ and Wnt did not require the presence of a Smad binding element, nor did it occur when a TGFβ-responsive reporter plasmid (p3TP-lux) was transfected. Overexpression of Smad 3 further enhanced the cooperation between Wnt and TGFβ while overexpression of dominant-negative Smads 2 and 3 inhibited this effect. Co-stimulation with TGFβ led to greater nuclear translocation of β-catenin, providing explanation for the effect of TGFβ on Wnt-3a reporter activity. Wnt-3a exerted antiproliferative activity in MEMM cells, similar to that exerted by TGFβ. In addition, Wnt-3a and TGFβ in combination led to synergistic decreases in MEMM cell proliferation. These data demonstrate a functional interaction between the TGFβ and Wnt signaling pathways and suggest that Wnt activation of the canonical pathway is an important mediator of MEMM cell growth.
Journal: FEBS Letters - Volume 579, Issue 17, 4 July 2005, Pages 3539–3546