A ceramide-activated protein phosphatase mediates ceramide-induced G1 arrest of Saccharomyces cerevisiae.
Certain mammalian growth modulators, such as tumor necrosis factor alpha, interleukin-1beta, and gamma-interferon, induce an antiproliferative response-terminal differentiation, apoptosis, 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.
Nickels
J T
JT
Department of Molecular Biology, Princeton University, New Jersey 08544, USA.
Broach
J R
JR
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002852:Chromatography, Ion Exchange; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005434:Flow Cytometry; D005656:Fungal Proteins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D005800:Genes, Fungal; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000201:enzymology / Q000235:genetics; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D005656:Fungal Proteins; D008565:Membrane Proteins; C064769:N-acetylsphingosine; D010749:Phosphoprotein Phosphatases; D013110:Sphingosine