TRANSGENIC MODELS FOR PROLIFERATIVE AND HYPERFUNCTIONAL THYROID-DISEASES

Mouse transgenic models that develop thyroid diseases were generated. All transgenes were driven by the thyroid specific promoter of the thy roglobulin gene. The tissue specificity of the promoter was investigat ed by using the bacterial chloramphenicol acetyl transferase gene as r eporter. The expression of an adenosine A2a receptor resulted in the p ermanent activation of the cAMP cascade. As a consequence, the transge nic mice developed severe hyperthyroidism and a large goiter, demonstr ating in vivo the role of the cAMP cascade in the promotion of both fu nction and proliferation of the thyroid cell. These mice constitute a model for autonomous hyperfunctional adenoma and nonautoimmune familia l hyperthyroidism, where mutant thyrotropin receptors stimulate the cA MP cascade constitutively. In another transgenic model, the function o f the retinoblastoma susceptibility gene product RB1 (and of related p roteins) was inhibited by expression of the E7 oncoprotein of human pa pillomavirus type 16. The result was the development of a differentiat ed and normofunctional colloid goiter, with the progressive developmen t of differentiated malignant lesions. This model suggests the essenti al role of RB1 and related proteins in the negative control of prolife ration that characterizes thyroid cells in the adult. Other transgenic models of thyroid diseases are discussed.