Lovastatin triggers an apoptosis-like cell death process in the fungus Mucor racemosus

The filamentous dimorphic fungus Mucor racemosus possesses three ras genes, Mras1, 2, and 3, whose expression is correlated to morphogenesis of the fu ngus, Lovastatin, an indirect inhibitor of protein prenylation, altered the processing of MRas1 protein, blocked the accumulation of MRas3 protein, an d caused the MRas1/ p20 protein complex to disappear in M. racemosus. Concu rrently it arrested sporangiospore germination, decreased growth rate, caus ed a loss of cell viability accompanied by cell shrinkage, increased cell d ensity and cytoplasm condensation, and triggered DNA fragmentation, resulti ng in nucleosomes and nucleosome multimers. The specific morphological and biochemical events seen in Mucor cell death, particularly DNA fragmentation , resemble the best known characteristics of classical apoptosis in mammali an cells and prompted us to classify lovastatin-induced cell death as an ap optosis-like process, Lovastatin did not cause cell death in a leucine auxo troph of Mucor grown in YNB minimal medium, conditions which support only s pherical growth during spore germination, Exogenous dibutyryl-cAMP initiate d morphogenesis from hyphal (polar] growth to yeast-like (spherical) growth during spore germination and strongly prevented cell death which resulted from lovastatin treatment. Wortmannin added together with dibutyryl-cAMP sh owed a synergistic effect in the prevention of fungal cell death. These dat a suggest that the regulation of lovastatin-induced cell death in Mucor req uires a signal transduction pathway(s) involving cAMP whose function is spe cific to a particular developmental stage. (C) 1998 Academic Press.