Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells.
TSH receptor mutants in the VI transmembrane segment, found in thyroid autonomously functioning adeonomas, have been expressed in differentiated thyroid cells. All mutant receptors constitutively stimulated adenylyl cyclase. The biological activity, measured as cAMP production relative to the wild type receptor, was specific for each mutant in transient and stable transfection assays. Cells expressing these mutants proliferated in the absence of TSH. The rate of growth in the absence of TSH paralleled basal cAMP production for each mutant receptor. Low TSH concentrations stimulated the growth of mutant receptor-expressing cells, and not of the cells expressing the wild type receptor. Also, the entry in the cell cycle and the plating efficiency were markedly stimulated by the expression of the mutant receptors. These data provide a molecular link between the occurrence of TSH receptor mutations and thyroid autonomously functioning adenomas.
Porcellini
A
A
Istituto Nazionale dei Tumori, Fondazione G Pascale, Napoli & Dipartimento di Biologia e Patologia Molecolare e Cellulare L Califano, Facoltà di Medicina, Università Federico II, Italy.
Ruggiano
G
G
Pannain
S
S
Ciullo
I
I
Amabile
G
G
Fenzi
G
G
Avvedimento
E V
EV
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D019556:COS Cells; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006801:Humans; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D013972:Thyrotropin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D012333:RNA, Messenger; D011989:Receptors, Thyrotropin; D013972:Thyrotropin; D000242:Cyclic AMP