Activating mutations of the Gsα gene are associated with low levels of Gsα protein in growth hormone-secreting tumors

Evidence suggests the existence of a direct relationship between cellular G(s)alpha content and activation of the adenylyl cyclase system. Data on G(s)alpha levels in endocrine tumors that depend an cAMP far growth, particularly pituitary adenomas, are still limited. The levels of G(s)alpha protein were evaluated in 11 GH-secreting adenomas with G(s)alpha mutations (gsp(+)) and 15 without (gsp). Complementary DNAs from gsp(+) tumors contained very low amounts of wild-type G(s)alpha sequences, indicating a preponderance of the mutant G(s)alpha transcripts in these tumors. Immunoblotting of G(s)alpha or protein showed that the two isoforms mere present at high levels in all gsp(-), but were undetectable or barely reduction in ribonucleic acid synthesis or stability, as G(s)alpha messenger ribonucleic acid levels were similar in wild-type and mutant tissues. Treatment of gsp(-) cells with cholera toxin caused a marked reduction of G(s)alpha levels. As in other cell systems cholera toxin increases G(s)alpha degradation, our data are consistent with an accelerated removal of mutant G(s)alpha. This may represent an additional mechanism of feedback response to the constitutive activation of cAMP signaling in pituitary tumors with mutations in the G(s)alpha gene.