G-PROTEIN ONCOGENES IN ACROMEGALY

G-proteins belong to a family of proteins which share the common prope rties of GTP binding and hydrolysis. Heterotrimeric G-proteins are com posed of alpha-, beta- and gamma-subunits. The alpha-subunit which dif fers from one G-protein to another contains the GDP/GTP binding site a nd has intrinsic GTPase activity. The receptor occupancy causes displa cement of bound GDP by GTP, dissociation of free betagamma-dimer and a lpha-GTP complex, interaction of the activated alpha-GTP complex with intracellular effectors, such as enzymes and ion channels. The turn of f of the reaction is due to the GTPase activity which causes the hydro lysis of GTP to GDP. G-proteins are essential for transferring hormona l signals from cell surface receptors to intracellular effectors. Sinc e G-proteins generate intracellular effectors involved in cell growth, G-protein genes have the propensity to be converted into oncogenes. I n fact, mutations in the alpha-subunit of Gs (the G-protein involved i n the activation of adenylyl cyclase) have been demonstrated in 40% of human GH secreting pituitary adenomas. Single amino acid substitution s replacing Arg 201 with either Cys or His or Gln 227 with either Arg or Leu cause constitutive activation of adenylyl cyclase by inhibiting GTPase (gsp oncogene). The same mutations were identified in about 10 % of thyroid adenomas and in the McCune-Albright syndrome.