CONSTITUTIVE ACTIVATION OF THE G(S)ALPHA PROTEIN-ADENYLATE CYCLASE PATHWAY MAY NOT BE SUFFICIENT TO GENERATE TOXIC THYROID ADENOMAS

In toxic thyroid adenomas, mutations in the TSH receptor (TSH-R) gene or the gene encoding the alpha-subunit of the stimulatory guanine nucl eotide-binding protein (G(s) alpha) have been demonstrated to constitu tively activate the cAMP cascade, which subsequently stimulates the gr owth and function of these tumors. However, the widely varying thyroid phenotypes in patients with TSH-R germline mutations, ranging from on ly slightly enlarged diffuse to multinodular goiters, suggest that add itional mechanisms may be effective in the pathogenesis of toxic adeno mas. We have investigated the levels of stimulatory and inhibitory G p rotein alpha-subunits together with basal and TSH-stimulated adenylate cyclase (AC) activity in toxic adenomas with or without activating mu tations and in nodular and extranodular tissues of a toxic goiter due to a germline mutation in the TSH-R gene. Augmented expression of G(s) alpha protein was detected in all toxic adenomas, independent of the presence of mutations, and in the nodular tissue of the toxic goiter, but not in the nonnodular hyperplastic tissue of the toxic goiter with the mutated TSH-R. Analogously, the expression of the alpha-subunit o f the inhibitory G protein (G(i) alpha) was also increased in all aden omas and the nodular tissue of the goiter, but, again, not in the hype rplastic goiter tissue. Basal AC activity was high in all tissues with mutations, but was only slightly increased in adenomas without detect ed mutations. No correlation was detectable between basal or TSH-stimu lated AC activity and the levels of G(s) alpha and G(i) alpha. Our dat a suggest that mutational activation of the cAMP cascade may not be su fficient to generate toxic nodules and adenomas, but far more complex mechanisms, including alterations of G protein signaling, may be effec tive in the pathogenesis of these tumors.