title: TGF-β promotes proliferation of thyroid epithelial cells in IFN-γ(-/-) mice by down-regulation of p21 and p27 via AKT pathway.
abstract: IFN-γ(-/-) NOD.H-2h4 mice develop an autoimmune disease characterized by hyperplasia and proliferation of thyroid epithelial cells (TEC H/P). Proliferating TECs produce TGF-β, and IFN-γ inhibits TEC H/P. In the present study, cultured TECs were used to directly determine the mechanisms by which these cytokines act on TECs to result in proliferation or inhibition of proliferation. With TECs from IFN-γ(-/-) NOD.H-2h4 mice or mice expressing the dominant negative TGF-β type II receptor on TECs, TGF-β was shown to promote TEC proliferation and IFN-γ was shown to inhibit TEC proliferation in vitro. TGF-β may promote TEC proliferation by down-regulating antiproliferative molecules p21 and p27, whereas IFN-γ may inhibit proliferation by up-regulating antiproliferative molecules p18 and p21 and down-regulating the pro-proliferative molecule cyclin D. Inhibition of AKT abolished the effect of TGF-β on p21 and p27, resulting in similar proliferation of TGF-β-treated and control TECs. Increased expression of proliferating cell nuclear antigen (PCNA), TGF-β, and p-AKT and decreased expression of p21 and p27 by proliferating TECs correlated with the proliferative state of TEC H/P. Taken together, the results suggest that TGF-β promotes TEC proliferation by down-regulating p21 and p27 via the AKT pathway in IFN-γ(-/-) NOD.H-2h4 mice, which may have significant implications for development of effective therapeutic strategies targeting the TGF-β and AKT pathways for treatment of hyperplasia and/or neoplasia.
authors: Department of Internal Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
authors: Yujiang
authors: Y
authors: Fang
authors: Shiguang
authors: S
authors: Yu
authors: Helen
authors: H
authors: Braley-Mullen
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency*; D051379:Mice; D016688:Mice, Inbred NOD; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D015398:Signal Transduction / Q000502:physiology; D013961:Thyroid Gland / Q000166:cytology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007371:Interferon-gamma; C514862:Akt1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077294:Receptor, Transforming Growth Factor-beta Type II