TREATMENT OF THE BUDDING YEAST SACCHAROMYCES-CEREVISIAE WITH THE LIPID-PEROXIDATION PRODUCT 4-HNE PROVOKES A TEMPORARY CELL-CYCLE ARREST ING(1) PHASE

The effects of 4-hydroxy-2-nonenal (HNE) on the cell division cycle we re investigated in the yeast Saccharomyces cerevisiae. A short treatme nt with HNE at a concentration in the range of the IC50 value in S. ce revisiae SP-4 cells induced a significant increase in the proportion o f G(0)/G(1) cells at the expense of S-phase cells. A similar delay in cell cycle progression upon treatment with HNE has recently been shown for HL-60 neoplastic cells. Long-term exposure in a synchronized yeas t culture resulted in a pronounced dose-dependent block between G(0)/G (1)- and S-phase, probably at or close to a point in the cell cycle th at has been designated as ''START.'' Incorporation of radioactively la beled precursors of macromolecules revealed that DNA synthesis was mos t susceptible to HNE in comparison to RNA and protein synthesis. Produ ction of glutathione appeared to be required for the continuation of t he cell cycle. HNE-treated yeast cells reentered the cell cycle when t heir glutathione content exceeded about twice the level of control cel ls. The release from the cell division cycle delay was followed by an enhanced growth to an extent that HNE-treated cells exceeded the numbe r of control cells. These results indicate that HNE causes a biphasic modulation of cell proliferation. It was concluded that this effect wa s conserved during evolution from yeast to mammalian cells, emphasizin g once more the usefulness of this unicellular organism as a model sys tem for the investigation of the effects of free radical-derived produ cts on the proliferation of eukaryotes. (C) 1998 Elsevier Science Inc.