title: Transforming growth factor-β activates c-Myc to promote palatal growth.
abstract: 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) β isoforms (1, 2, and 3) throughout these steps of palatogenesis. However, the role of TGFβ in promoting proliferation of palatal mesenchymal cells has never been explored. The purpose of this study was to identify the effect of TGFβ on human embryonic palatal mesenchymal (HEPM) cell proliferation. Our results showed that all isoforms of TGFβ, especially TGFβ3, increased HEPM cell proliferation by up-regulating the expression of cyclins and cyclin-dependent kinases as well as c-Myc oncogene. TGFβ 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 TGFβ, 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 TGFβ signaling, which is essential for complete palatal confluency. Our data highlights the potential role of TGFβ as a therapeutic molecule to correct cleft palate by promoting growth.
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68512, USA.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Zhu
authors.forename: Ferhat
authors.initials: F
authors.lastname: Ozturk
authors.forename: Changchih
authors.initials: C
authors.lastname: Liu
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Oakley
authors.forename: Ali
authors.initials: A
authors.lastname: Nawshad
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010159:Palate / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000378:metabolism / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D053782:Transforming Growth Factor beta3 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018797:Cell Cycle Proteins; C489427:MYC protein, human; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D053782:Transforming Growth Factor beta3; D018844:Cyclin-Dependent Kinases