A ceramide-activated protein phosphatase mediates ceramide-induced G₁ arrest of Saccharomyces cerevisiae

Certain mammalian growth modulators, such as tumor necrosis factor α, interleukin-1β, and γ-interferon, induce an antiproliferative response-terminal differentiation, apoptosisis, or cell cycle arrest-through a novel signal transduction pathway mediated by the lipid ceramide as a second messenger. Both a ceramide-activated protein phosphatase and a ceramide-activated protein kinase have been implicated in transmitting the signals elicited by ceramide. We have determined that ceramide addition to the yeast Saccharomyces causes a similar antiproliferative response, resulting in arrest of cells in the G₁ phase of the cell cycle. We have also determined that yeast cells contain a ceramide-activated protein phosphatase composed of regulatory subunits encoded by TPD3 and CDC55 and a catalytic subunit encoded by SIT4, Because mutation of any one of these three genes renders strains resistant to ceramide inhibition, we conclude that the G₁ effects of ceramide are mediated at least in part by the yeast ceramide-activated protein phosphatase. These results highlight the conservation of signaling systems in yeast and mammalian cells and provide a novel approach to dissecting this ubiquitous signal transduction pathway.