[G-proteins and endocrine tumors. The example of acromegaly]

Mutations of Gs are found in 30 to 40% of the pituitary tumours responsible for acromegaly (somatotrope tumor), 10% of secreting thyroid tumors, and in the rare McCune-Albright syndrome. Gs is a member of the G protein family, which plays a major role in the mechanism of action of many hormones by coupling their membrane receptors to molecules called effectors, which general intracellular second messengers. Gs is responsible for the coupling of many receptors to adenylate cyclase which synthetizes cyclic AMP. The effect of the mutations of Gs is to permanently activate adenylate cyclase by a mechanism similar to the one exerted by cholera toxin. In the somatotrope cells adenylate cyclase is normally under the control of the hypothalamic hormone GH-RH, which stimulates both growth hormone secretion and cell proliferation. The mutations of Gs allow the somatotrope to escape from the control by GH-RH and to secrete and proliferate in an autonomous way, which leads to the development of a tumor responsible for acromegaly. The same mechanism explains the presence of Gs mutations in the other types of endocrine tumors. Therefore, the mutations transform the gene of Gs into an oncogene, gsp, which represents the first molecular explanation of an old concept familiar to endocrinologists: the autonomy of the secretion and proliferation of endocrine tumors.