Two G Protein Oncogenes in Human Endocrine Tumors

Abstract

Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the alpha polypeptide chain (alpha s) of Gs into a putative oncogene, termed gsp. These mutations, which activate alpha 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 alpha 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 alpha chain genes. The first gene so far tested, which encodes the alpha chain of Gi2, 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 alpha 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 alpha chain genes.

Regulation of cell proliferation by G proteins

“…Therefore, the observation that the Ga s -mediated signaling pathway is constitutively activated in a subset of human pituitary tumors (Vallar et al, 1987) led to an intense search for the activating mutations of Ga s in endocrine tumors. Point mutations in the a s subunit involving the replacement of either arginine 201 (R201) or glutamine 227 (Q227) were identi®ed as the activating mutations involved in pituitary GH secreting tumors and thyroid hyperfunctioning adenomas (Landis et al, 1989;Lyons et al, 1990). Accordingly, the mutationally activated form of Ga s is known as the gsp oncogene (derived from Gs protein).…”

“…Mutations in these residues have been observed in di erent forms of tumors. While R179-mutation of Ga i2 was identi®ed in ovarian sex cord stromal tumors and adrenal cortex tumors (Lyons et al, 1990), Q205- Figure 1 Schematic model for the regulation of cell proliferation by G proteins. Stimulation of a receptor coupled to a speci®c G protein generates both a-speci®c and bg-speci®c signals as illustrated whereas the activated (GTPase-de®cient) a-subunit stimulates only the a-speci®c events (see text for details).…”

Cyclic AMP activates Ras

“…Mutations that give rise to constitutive activity of cAMPmediated signaling pathways have been identi®ed in human tumors. Mutations in Gas (Lyons et al, 1990;Suarez et al, 1991) and in the TSH receptor (Parma et al, 1993) that result in constitutive activation of cAMP-mediated signaling are prevalent in human thyroid tumors. Despite this, very little is known regarding how cAMP elicits proliferation in some cells and impairs it in others.…”

Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells

“…A molecular basis for the TSH-independent growth and function of these tumours has been recently found: some of these tumours have somatic mutations in the alpha subunit of heterotrimeric G-protein (G s a) coupled to the TSH receptor, which stimulates the adenylyl cyclase (Lyons et al, 1990;O'Sullivan et al, 1991;Suarez et al, 1991). In other cases of thyroid hyperfunctioning adenomas activating mutations of the TSH receptor have been found in the III8 intracellular loop of the receptor (Parma et al, 1993).…”