[Transgenic mouse models. Their interest in thyroid tumors]

Abstract

Mouse transgenic models that develop thyroid diseases were generated. All transgenes were driven by the thyroid specific promoter of the thyroglobulin gene. The tissue specificity of the promoter was investigated by using the bacterial chloramphenicol acetyltransferase gene as reporter. The expression of the adenosine A2a receptor resulted in the permanent activation of the cAMP cascade. As a consequence, transgenic mice developed severe hyperthyroidism and a large goiter, demonstrating in vivo the role of the cAMP cascade in the promotion of both function and proliferation of the thyroid cell. These mice constitute a model for autonomous hyperfunctional adenoma and non autoimmune familial hyperthyroidism, where mutant of thyrotropin receptors stimulate the cAMP cascade constitutively. The expression of a mutant of the alpha 1B adrenergic receptor resulted in the constitutive activation of both the cAMP and IP3-CA++ cascades, growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals, and development of malignancies. The expression of the SV40 large T antigen promoted the development of aggressive undifferentiated tumors mimicking the phenotype of human anaplastic carcinomas and embryonal tumors. In another transgenic model, the function of the retinoblastoma susceptibility gene product RB1 (and of related proteins) was inhibited by expressing the E7 oncoprotein of human papillomavirus type 16. The result was the development of a differentiated and normofunctional colloid goiter, with progressive development of differentiated malignant lesions. This model suggests the essential role of RB1 and related proteins in the negative control of proliferation that characterizes thyroid cells in the adult. Other transgenic models of thyroid diseases are discussed.