Transforming growth factor-β activates c-Myc to promote palatal growth

During palatogenesis, the palatal mesenchyme undergoes increased cell proliferation resulting in palatal growth, elevation and fusion of the two palatal shelves. Interestingly, the palatal mesenchyme expresses all three transforming growth factor (TGF) isoforms (1, 2, and 3) throughout these steps of palatogenesis. However, the role of TGF beta in promoting proliferation of palatal mesenchymal cells has never been explored. The purpose of this study was to identify the effect of TGF beta on human embryonic palatal mesenchymal (HEPM) cell proliferation. Our results showed that all isoforms of TGF beta, especially TGF beta 3, increased HEPM cell proliferation by up-regulating the expression of cyclins and cyclin-dependent kinases as well as c-Myc oncogene. TGF beta activated both Smad-dependent and Smad-independent pathways to induce c-Myc gene expression. Furthermore, TBE1 is the only functional Smad binding element (SBE) in the c-Myc promoter and Smad4, activated by TGF beta, binds to the TBE1 to induce c-Myc gene activity. We conclude that HEPM proliferation is manifested by the induction of c-Myc in response to TGF beta signaling, which is essential for complete palatal confluency. Our data highlights the potential role of TGF beta as a therapeutic molecule to correct cleft palate by promoting growth. J. Cell. Biochem. 113: 30693085, 2012. (c) 2012 Wiley Periodicals, Inc.