THYROID-SPECIFIC EXPRESSION OF CHOLERA-TOXIN A1 SUBUNIT CAUSES THYROID HYPERPLASIA AND HYPERTHYROIDISM IN TRANSGENIC MICE

Thyroid cell growth and function are regulated by hormones and growth factors binding to cell surface receptors that are coupled via G prote ins, Gs and Gq, to the adenylyl cyclase and phospholipase C signal tra nsduction systems, respectively. Activating mutations of the TSH recep tor and Gas have been documented in subsets of thyroid neoplasms. To t est the oncogenic potential of activated Gels in transgenic mice, we u sed the cholera toxin Al subunit that constitutively activates G alpha s and used the rat thyroglobulin gene promoter for targeting this tra nsgene (TGCT) to thyroid follicular cells. Three (M1392, F1358, and F1 286) of six founders identified were able to transmit the transgene to their offspring and thyroid glands from these mice contained elevated levels of cAMP. Concentrations of serum thyroxine were elevated as ea rly as 2 months of age (M 1392 and F 1286). F1358 mice were euthyroid until 8 months of age, at which time they developed hyperthyroidism. A ll three TGCT lines developed thyroid hyperplasia independent of their thyroxine levels. DNA image analysis of thyroid follicular cells from both the hyper and euthyroid mice showed that DNA index and ''S+G2/M' ' phase were increased compared with normal, changes similar to that s een in poor prognosis human carcinomas. These data suggest that the Ga s-adenylyl cyclase-cAMP pathway has an important role in thyroid hyper plasia and the transgenic mouse models reported herein will allow furt her examination of the role of this pathway in thyroid oncogenesis.