[Transgenic models of human thyroid pathologies: hyperfunctional adenoma, anaplastic cancer, differentiated cancer, hypothyroidism].
Bovine thyroglobulin gene upstream regulatory sequences were used as a tissue specific promoter in order to direct the expression of different genes specifically to the thyroid gland. Transgenic models of thyroid diseases have been generated, by directing the expression of specific oncogenes to the thyroid cell. In one of these models (TgAgT), the sv40 large T antigen promoted the development of an aggressive undifferentiated tumor mimicking the phenotype of the human anaplastic carcinoma. In the second model (TgA2aR), the expression of the adenosine A2 alpha receptor, acting as a constitutive activator of adenylyl cyclase, resulted in the development of a hyperfunctioning goiter, and in old animals to the formation of malignant foci. Transgenic lines expressing the E6 oncogenic (TgE6) from type 16 human papillomavirus appeared to be asymptomatic. In contrast, the thyroid cells of mice expressing E7 oncogene divide very rapidly, but remain differentiated, resulting in the development of huge colloid goiters. Signs of malignancy appear late in the development. The molecular properties of E6 and E7 oncogenes are to bind, and inactivatc, the tumor suppressor gene producers p53 (E6), or RB (E7). Our transgenic models indicate that the RB protein (and/or related proteins) are essential factors in the negative control of thyroid cell proliferation. On the contrary, inactivation of p53 seems to play a minor role, at least in the early steps of tumor formation. In the last model (Tg alpha 1B), the expression of a mutant of the alpha 1B adrenergic receptor reported to activate both CAMP and sigma P3-CA-cascades, resulted in growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals and malignancy.
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D000818:Animals; D030801:Animals, Genetically Modified; D002277:Carcinoma / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000235:genetics; D016158:Genes, p53; D006042:Goiter / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D013954:Thyroglobulin / Q000235:genetics; D013959:Thyroid Diseases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
D013954:Thyroglobulin