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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 12 4386-4390
Copyright © 1998 by The Endocrine Society

Original Studies

Activating Mutations of the Gs{alpha} Gene Are Associated with Low Levels of Gs{alpha} Protein in Growth Hormone-Secreting Tumors1

Emilia Ballaré, Simona Mantovani, Andrea Lania, Anna M. Di Blasio, Lucia Vallar and Anna Spada

Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, Italian Auxologic Center IRCCS (A.M.D.B.), and the Department of Pharmacology, CNR Center of Cytopharmacology, Scientific Institute San Raffaele, University of Milan (L.V.), Milan, Italy

Address all correspondence and requests for reprints to: Anna Spada, M.D., Istituto di Scienze Endocrine Ospedale Maggiore, IRCCS, Via Francesco Sforza 35, 20122 Milan, Italy. E-mail: endosci{at}imiucca.csi unimi.it.

Evidence suggests the existence of a direct relationship between cellular Gs{alpha} content and activation of the adenylyl cyclase system. Data on Gs{alpha} levels in endocrine tumors that depend on cAMP for growth, particularly pituitary adenomas, are still limited. The levels of Gs{alpha} protein were evaluated in 11 GH-secreting adenomas with Gs{alpha} mutations (gsp+) and 15 without (gsp). Complementary DNAs from gsp+ tumors contained very low amounts of wild-type Gs{alpha} sequences, indicating a preponderance of the mutant Gs{alpha} transcripts in these tumors. Immunoblotting of Gs{alpha} protein showed that the two isoforms were present at high levels in all gsp-, but were undetectable or barely detectable in gsp+. The low Gs{alpha} content in gsp+ tumors was not due to a reduction in ribonucleic acid synthesis or stability, as Gs{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 Gs{alpha} levels. As in other cell systems cholera toxin increases Gs{alpha} degradation, our data are consistent with an accelerated removal of mutant Gs{alpha}. This may represent an additional mechanism of feedback response to the constitutive activation of cAMP signaling in pituitary tumors with mutations in the Gs{alpha} gene.




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