Two G Protein Oncogenes in Human Endocrine Tumors

TLDR

Somatic mutations in GH‑secreting pituitary tumors convert the Gs α subunit into the oncogene gsp by inhibiting its GTPase activity at two conserved residues. The study aimed to determine whether analogous activating mutations occur in other G protein α chains. It surveyed human tumors for mutations that replace the conserved residues in these G protein α chains. Mutations activating G i2 (gip2) were found in adrenal and ovarian tumors, while gsp mutations were also detected in GH‑secreting pituitary tumors and a thyroid adenoma, suggesting that various G protein α chain genes can harbor oncogenic mutations in human tumors.

Abstract

Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the α polypeptide chain (α s ) of G s into a putative oncogene, termed gsp . These mutations, which activate α s by inhibiting its guanosine triphosphatase (GTPase) activity, are found in codons for either of two amino acids, each of which is completely conserved in all known G protein α chains. The likelihood that similar mutations would activate other G proteins prompted a survey of human tumors for mutations that replace either of these two amino acids in other G protein α chain genes. The first gene so far tested, which encodes the α chain of G i2 , showed mutations that replaced arginine-179 with either cysteine or histidine in 3 of 11 tumors of the adrenal cortex and 3 of 10 endocrine tumors of the ovary. The mutant α i2 gene is a putative oncogene, referred to as gip2 . In addition, gsp mutations were found in 18 of 42 GH-secreting pituitary tumors and in an autonomously functioning thyroid adenoma. These findings suggest that human tumors may harbor oncogenic mutations in various G protein α chain genes.