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)α content and activation of the adenylyl cyclase system. Data on G(s)α levels in endocrine tumors that depend on cAMP for growth, particularly pituitary adenomas, are still limited. The levels of G(s)α protein were evaluated in 11 GH-secreting adenomas with G(s)α mutations (gsp+) and 15 without (gsp). Complementary DNAs from gsp+ tumors contained very low amounts of wild-type G(s)α sequences, indicating a preponderance of the mutant G(s)α transcripts in these tumors. Immunoblotting of G(s)α protein showed that the two isoforms were present at high levels in all gsp- , but were undetectable or barely detectable in gsp+. The low G(s)α content in gsp+ tumors was not due to a reduction in ribonucleic acid synthesis or stability, as G(s)α 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)α levels. As in other cell systems cholera toxin in creases G(s)α degradation, our data are consistent with an accelerated removal of mutant G(s)α. 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)α gene.