Anti-mitogenic function of interferon-induced (2'-5')oligo(adenylate) and growth-related variations in enzymes that synthesize and degrade this oligonucleotide.

Addition of (2'5')ApApA to concanavalin-A-stimulated mouse spleen lymphocytes strongly inhibits the large increase in RNA and protein synthesis which takes place 24-48 h after stimulation. The inhibitory effect on protein synthesis precedes the effect on RNA synthesis and takes at least 6 h to be detected. Histone synthesis is preferentially inhibited at 48 h. No effect on protein synthesis was detected in unstimulated resting lymphocytes, or in stimulated lymphocytes during the first 24 h after concanavalin A treatment. The anti-mitogenic effect of the (2'-5')oligo(adenylate) seems to result, therefore, from inhibition of protein synthesis taking place before initiation of DNA replication. The mitogenic stimulus produced by the lectin enhances, in lymphocytes, the level of the 2'-phosphodiesterase which degrades (2'-5')oligo(adenylate). Enhancement of the 2'-phosphodiesterase was also observed after serum stimulation of confluent monkey kidney cells. Furthermore, the ratio of (2'-5')oligo(adenylate) synthetase to 2'-phosphodiesterase is ten-times lower in fast-growing kidney cells than in quiescent serum-starved cells. A model for the role of (2'-5')oligo(adenylate) synthesis and degradation in the regulation of cell proliferation by interferon and by mitogens is presented.