title: Effects of the Smad4 C324Y mutation on thyroid cell proliferation.
abstract: Smad4 is a key mediator of the transforming growth factor-β (TGF-β) superfamily that is involved in the control of cell proliferation and differentiation. We recently demonstrated that a Smad4 mutation, Smad4 C324Y, isolated from nodal metastases of papillary thyroid carcinoma, causes an increase of TGF-β signaling, responsible for the acquisition of transformed phenotype and invasive behaviour in thyroid cells stably expressing this mutation. In this paper, we demonstrate that the stable expression of Smad4 C324Y mutation in FRTL-5 cells is responsible for TSH-independent growth ability. Our data show that the Smad4 C324Y mutation interacts with P-Smad3 more strongly than Smad4 wt, already in basal condition; this interaction is responsible for TGF-β signaling and PKA activation that, in turn, determines an increased phosphorylation of CREB, necessary for the mitogenic actions of TSH. The expression of cyclin D1 also increases in all cells overexpressing the Smad4 C324Y mutation. All together, these data demonstrate that Smad4 C324Y mutation, interacting with the PKA pathway, gives cells the ability to proliferate independently from TSH.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, I-324-00161 Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: D'Inzeo
authors.forename: Arianna
authors.initials: A
authors.lastname: Nicolussi
authors.forename: Francesco
authors.initials: F
authors.lastname: Nardi
authors.forename: Anna
authors.initials: A
authors.lastname: Coppa
mesh_terms: D002277:Carcinoma / Q000235:genetics*; D002291:Carcinoma, Papillary; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D013954:Thyroglobulin / Q000235:genetics / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000166:cytology* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics*; D013972:Thyrotropin / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D013972:Thyrotropin; D013954:Thyroglobulin; D017868:Cyclic AMP-Dependent Protein Kinases