Activating mutations of the α subunit of the G protein G(s) (G(s)α) have been identified in thyroid adenomas and well-differentiated thyroid carcinomas. To examine the role of activating mutations of G(s)α in thyroid neoplasia, we transfected rat follicular thyroid (FRTL-5) cells with a transgene in which the cholera toxin A1 subunit (CTA1) is expressed under the control of the rat thyroglobulin gene promoter (TG). This transgene recapitulates effects of the activating mutation of G(s)α its ability to ADP-ribosylate and thereby inhibit GTPase activity of endogenous G(s)α molecules. To assess the effect of G(s)α activation on cell growth, TGCTA1, or control, pM AM neotransfected FRTL-5 cells (104-106) were injected sc into nude mice. TGCTA1-transfected FRTL-5 cells grow in nude mice, whereas control cells do not. Tumor histology revealed increased mitotic activity, infiltration oF skeletal muscle, perineural invasion, and plugging of lymphatic spaces. In addition, nude mice injected with TGCTA1 transfected cells or xenografted with the tumors developed metastases to lung. These results indicate that activation of G(s)α and constitutive production of cAMP in FRTL-5 cells can result in TSH-independent cellular proliferation and neoplastic transformation.
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