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 fungus. Lovastatin, an indirect inhibitor of protein prenylation, altered the processing of MRas1 protein, blocked the accumulation of MRas3 protein, and caused the MRas1/p20 protein complex to disappear in M. racemosus. Concurrently it arrested sporangiospore germination, decreased growth rate, caused a loss of cell viability accompanied by cell shrinkage, increased cell density and cytoplasm condensation, and triggered DNA fragmentation, resulting 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 mammalian cells and prompted us to classify lovastatin-induced cell death as an apoptosis-like process. Lovastatin did not cause cell death in a leucine auxotroph of Mucor grown in YNB minimal medium, conditions which support only spherical growth during spore germination. Exogenous dibutyryl-cAMP initiated 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 showed a synergistic effect in the prevention of fungal cell death. These data suggest that the regulation of lovastatin-induced cell death in Mucor requires a signal transduction pathway(s) involving cAMP whose function is specific to a particular developmental stage.
Roze
L V
LV
Department of Food Science and Human Nutrition, Michigan State University, East Lansing 48824, USA.
Linz
J E
JE
D000730:Androstadienes / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D017209:Apoptosis; D003994:Bucladesine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D053938:DNA Fragmentation; D005800:Genes, Fungal / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects; D007700:Kinetics; D008148:Lovastatin / Q000494:pharmacology*; D009089:Mucor / Q000166:cytology / Q000187:drug effects* / Q000235:genetics; D013110:Sphingosine / Q000494:pharmacology; D000077191:Wortmannin