ONCOGENIC POTENTIAL OF A MUTANT HUMAN THYROTROPIN RECEPTOR EXPRESSED IN FRTL-5 CELLS

An abnormal stimulation of the cAMP pathway has been recognized as the primary event in various pathological situations that lead to goitrog enesis or thyroid tumors, Thyroid adenomas are monoclonal neoplasms th at become independent of thyroid stimulating hormone (TSH) in their se cretory function and growth, Mutated forms of the TSH receptor (TSHR) and the adenylyl cyclase-activating Gs alpha protein, which confer a c onstitutive activity on these proteins, have been observed in human ad enomas, The FRTL-5 rat thyroid cell line is a permanent but untransfor med line; the growth of which depends on the presence of TSH, and at l east in part, on the stimulation of the cAMP pathway, In order to comp are the oncogenic potential of the activated mutant Gs alpha protein a nd the constitutively activated TSHR, we have transfected FRTL-5 cells with an expression vector bearing either the cDNA of the Gs alpha gen e carrying the A201S mutation or the cDNA of the TSH receptor carrying the M453T mutation recently identified in a case of congenital hypert hyroidism. The expression of these two cDNAs was driven by the bovine thyroglobulin gene promoter, We show that, although the expression of both the Gs alpha or TSHR mutant proteins leads to TSH-independent pro liferation and to constitutive cAMP accumulation in FRTL-5 cells, only the mutant TSHR is able to induce neoplastic transformation, as demon strated by growth in semi-solid medium and tumorigenesis in nude mice.