The cellular composition and concentration of fatty acids are crucial for proliferation and survival. We recently showed stimulation of protein phosphatase type-2C (PP2C) by unsaturated fatty acids. Here, we describe that treatment of cultured chick neurons with 100 microM oleic acid for 24h increased the percentage of damaged neurons to 61+/-9% compared with 25+/-4% in controls. Oleic acid-induced cell death showed features of apoptosis such as chromatin condensation, shrinkage of the nucleus, DNA fragmentation and caspase-3 activation. Extensive studies with a variety of fatty acids revealed a striking correlation between activation of PP2C and induction of apoptosis. Lipophilicity, oxidizability, and an acidic group were required for both effects. In addition, activation of PP2C and induction of apoptosis could discriminate between cis- and trans-conformation of the fatty acids. The results are in favor of PP2C playing an important, yet unidentified role in apoptosis.