RAPAMYCIN SPECIFICALLY INTERFERES WITH THE DEVELOPMENTAL RESPONSE OF FISSION YEAST TO STARVATION

Rapamycin is a microbial macrolide which belongs to a family of immuno suppressive drugs that suppress the immune system by blocking stages o f signal transduction in T lymphocytes. In Saccharomyces cerevisiae ce lls, as in T lymphocytes, rapamycin inhibits growth and cells become a rrested at the G(1) stage of the cell cycle. Rapamycin is also an effe ctive antifungal agent, affecting the growth of yeast and filamentous fungi. Unexpectedly, we observed that rapamycin has no apparent effect on the vegetative growth of Schizosaccharomyces pombe. Instead, the d rug becomes effective only when cells experience starvation. Under suc h conditions, homothallic wild-type cells will normally mate and under go sporulation. In the presence of rapamycin, this sexual development process is strongly inhibited and cells adopt an alternative physiolog ical option and enter stationary phase. Rapamycin strongly inhibits se xual development of haploid cells prior to the stage of sexual conjuga tion. In contrast, the drug has only a slight inhibitory effect on the sporulation of diploid cells. A genetic approach was applied to ident ify the signal transduction pathway that is inhibited by rapamycin. Th e results indicate that either rapamycin did not suppress the derepres sion of sexual development of strains in which adenylate cyclase was d eleted or the cyclic AMP dependent protein kinase encoded by pka1 was mutated. Nor did rapamycin inhibit the unscheduled meiosis observed in pat1-114 mutants. Overexpression of ras1(+), an essential gene for se xual development, did not rescue the sterility of rapamycin-treated ce lls. However, expression of the activated allele, ras1(Val17), antagon ized the effect of rapamycin and restored the ability of the cells to respond to mating signals in the presence of the drug. We discuss poss ible mechanisms for the inhibitory effect of rapamycin on sexual devel opment in S. pombe.