The ras oncogene product p21 is not a regulatory component of adenylate cyclase

Abstract

Harvey (Ha-MSV) and Kirsten (Ki-MSV) murine sarcoma viruses induce tumours in animals and transform various cells in culture because of the expression of the ras oncogene product, p21 (ref. 1). Proto-oncogenes homologous with these genes are highly conserved evolutionarily and activated ras oncogenes have been detected in many human cancers. Whether c-ras oncogenes are directly responsible for human carcinogenesis is uncertain; however, it is clear that p21 mediates virus-induced transformation, although by an unknown mechanism. Epithelial and fibroblast cell lines transformed with Ha-MSV and Ki-MSV express p21 (ref. 8) and exhibit reduced adenylate cyclase activity. Like the guanine nucleotide regulatory proteins, Ns and Ni, which mediate stimulation and inhibition, respectively, of adenylate cyclase, p21 is a membrane-associated GTP binding protein, which exhibits GTPase activity. These similarities suggest that p21 and the adenylate cyclase regulatory proteins are related in cellular function, and that p21 depresses adenylate cyclase by inhibiting the activity of Ns or acting as Ni. We have therefore now examined the structural and functional similarities between p21 and Ns and Ni and find no evidence that p21 regulates adenylate cyclase activity by acting as one of these regulatory proteins.

Ca+2 Signal is Generated Only Once in the Mating Pheromone Response Pathway in Saccharomyces cerevisiae.

“…Yeast Ras proteins, members of small G proteins, structurally resemble mammalian ras oncogene products (Powers et al, 1984). Unlike mammalian Ras proteins, however, yeast Ras proteins activate adenylate cyclase (Beckner et al, 1985;Toda et al, 1985). By contrast, in mammalian cells, adenylate cyclase is activated by heterotrimeric G proteins (Gilmann, 1987).…”

Identification of ras-related, YPT family genes in Schizosaccharomyces pombe.

“…Although human H-ras could apparently complement a S. cerevisiae rasdefective mutation DeFeo-Jones et al, 1985), the human gene has been shown not to be involved in the control of adenylate cyclase (Beckner et al, 1985;Birchmeier et al, 1985), whereas regulation of this enzyme is the major role of the S. cerevisiae ras proteins (Toda et al, 1985). Hence further analysis of the function of S.pombe YPT family genes in S.pombe cells appears to be critical.…”

Expression of p21 proteins in Escherichia coli and stereochemistry of the nucleotide-binding site.

“…Thus it has been postulated that these proteins have an analogous function to that which G-proteins and transducin have in the amplification of extracellular signals. The human Ha-ras oncogene product, however, is not a component of adenylate cyclase (Beckner et al, 1985) and it does not seem to be specifically ADP-ribosylated. In addition, in a recent report by Birchmeier et al (1985) it was shown that human Ha-ras p21 proteins injected into oocytes induce maturation but do not change the cyclic AMP concentration.…”