GTPase-inhibiting mutations activate the alpha-chain of Gs in human tumours

Several trophic hormones transmit their signals by coupling to G-proteins. A subset of human growth hormone (GH)-secreting pituitary tumours, characterized by elevated GH secretion, cyclic AMP levels, and adenylyl cyclase activity, carries mutations in the gene that encodes the alpha-chain of Gs. By substitution of a single amino acid (Arg-201 or Gln-227), these mutations inhibit the intrinsic GTPase activity of alpha s, thus stabilizing the protein in its active conformation. The discovery of mutant alpha s proteins in human tumours suggests that the alpha s gene can be converted into an oncogene, called gsp, in cells that proliferate in response to cyclic AMP. Most likely, oncogenes can result from similar mutations in other G-protein alpha-chain genes.