G-Protein Oncogenes in Acromegaly

Abstract

G-proteins belong to a family of proteins which share the common properties of GTP binding and hydrolysis. Heterotrimeric G-proteins are composed of α-, β- and γ-subunits. The α-subunit which differs from one G-protein to another contains the GDP/GTP binding site and has intrinsic GTPase activity. The receptor occupancy causes displacement of bound GDP by GTP, dissociation of free βγ-dimer and α-GTP complex, interaction of the activated α-GTP complex with intracellular effectors, such as enzymes and ion channels. The turn off of the reaction is due to the GTPase activity which causes the hydrolysis of GTP to GDP. G-proteins are essential for transferring hormonal signals from cell surface receptors to intracellular effectors. Since G-proteins generate intracellular effectors involved in cell growth, G-protein genes have the propensity to be converted into oncogenes. In fact, mutations in the α-subunit of Gs (the G-protein involved in the activation of adenylyl cyclase) have been demonstrated in 40% of human GH secreting pituitary adenomas. Single amino acid substitutions replacing Arg 201 with either Cys or His or Gin 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.