TY - JOUR
T1 - Constitutive Activation of the Gsα Protein-Adenylate Cyclase Pathway May Not Be Sufficient to Generate Toxic Thyroid Adenomas
AU - Derwahl, Michael
AU - Hamacher, Christiane
AU - Russo, Diego
AU - Broecker, Martina
AU - Manole, Diana
AU - Schatz, Helmut
AU - Kopp, Peter
AU - Filetti, Sebastiano
PY - 1996
Y1 - 1996
N2 - In toxic thyroid adenomas, mutations in the TSH receptor (TSH-R) gene or the gene encoding the α-subunit of the stimulatory guanine nucleotide-binding protein (Gsα) have been demonstrated to constitutively activate the cAMP cascade, which subsequently stimulates the growth and function of these tumors. However, the widely varying thyroid phenotypes in patients with TSH-R germline mutations, ranging from only slightly enlarged diffuse to multinodular goiters, suggest that additional mechanisms may be effective in the pathogenesis of toxic adenomas. We have investigated the levels of stimulatory and inhibitory G protein α-subunits together with basal and TSH-stimulated adenylate cyclase (AC) activity in toxic adenomas with or without activating mutations and in nodular and extranodular tissues of a toxic goiter due to a germline mutation in the TSH-R gene. Augmented expression of Gsα 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 α-subunit of the inhibitory G protein (Giα) was also increased in all adenomas and the nodular tissue of the goiter, but, again, not in the hyperplastic goiter tissue. Basal AC activity was high in all tissues with mutations, but was only slightly increased in adenomas without detected mutations. No correlation was detectable between basal or TSH-stimulated AC activity and the levels of Gsα and Giα. Our data suggest that mutational activation of the cAMP cascade may not be sufficient to generate toxic nodules and adenomas, but far more complex mechanisms, including alterations of G protein signaling, may be effective in the pathogenesis of these tumors.
AB - In toxic thyroid adenomas, mutations in the TSH receptor (TSH-R) gene or the gene encoding the α-subunit of the stimulatory guanine nucleotide-binding protein (Gsα) have been demonstrated to constitutively activate the cAMP cascade, which subsequently stimulates the growth and function of these tumors. However, the widely varying thyroid phenotypes in patients with TSH-R germline mutations, ranging from only slightly enlarged diffuse to multinodular goiters, suggest that additional mechanisms may be effective in the pathogenesis of toxic adenomas. We have investigated the levels of stimulatory and inhibitory G protein α-subunits together with basal and TSH-stimulated adenylate cyclase (AC) activity in toxic adenomas with or without activating mutations and in nodular and extranodular tissues of a toxic goiter due to a germline mutation in the TSH-R gene. Augmented expression of Gsα 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 α-subunit of the inhibitory G protein (Giα) was also increased in all adenomas and the nodular tissue of the goiter, but, again, not in the hyperplastic goiter tissue. Basal AC activity was high in all tissues with mutations, but was only slightly increased in adenomas without detected mutations. No correlation was detectable between basal or TSH-stimulated AC activity and the levels of Gsα and Giα. Our data suggest that mutational activation of the cAMP cascade may not be sufficient to generate toxic nodules and adenomas, but far more complex mechanisms, including alterations of G protein signaling, may be effective in the pathogenesis of these tumors.
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U2 - 10.1210/jcem.81.5.8626855
DO - 10.1210/jcem.81.5.8626855
M3 - Article
C2 - 8626855
AN - SCOPUS:0029664322
SN - 0021-972X
VL - 81
SP - 1898
EP - 1904
JO - Journal of clinical endocrinology and metabolism
JF - Journal of clinical endocrinology and metabolism
IS - 5
ER -