TY - JOUR
T1 - A chemogenomic screen in Saccharomyces cerevisiae uncovers a primary role for the mitochondria in farnesol toxicity and its regulation by the Pkc1 pathway
AU - Fairn, Gregory D.
AU - MacDonald, Kendra
AU - McMaster, Christopher R.
PY - 2007/2/16
Y1 - 2007/2/16
N2 - The isoprenoid farnesol has been shown to preferentially induce apoptosis in cancerous cells; however, the mode of action of farnesol-induced death is not established. We used chemogenomic profiling using Saccharomyces cerevisiae to probe the core cellular processes targeted by farnesol. This screen revealed 48 genes whose inactivation increased sensitivity to farnesol. The gene set indicated a role for the generation of oxygen radicals by the Rieske iron-sulfur component of complex III of the electron transport chain as a major mediator of farnesol-induced cell death. Consistent with this, loss of mitochondrial DNA, which abolishes electron transport, resulted in robust resistance to farnesol. A genomic interaction map predicted interconnectedness between the Pkc1 signaling pathway and farnesol sensitivity via regulation of the generation of reactive oxygen species. Consistent with this prediction (i) Pkc1, Bck1, and Mkk1 relocalized to the mitochondria upon farnesol addition, (ii) inactivation of the only non-essential and non-redundant member of the Pkc1 signaling pathway, BCK1, resulted in farnesol sensitivity, and (iii) expression of activated alleles of PKC1, BCK1, and MKK1 increased resistance to farnesol and hydrogen peroxide. Sensitivity to farnesol was not affected by the presence of the osmostabilizer sorbitol nor did farnesol affect phosphorylation of the ultimate Pkc1-responsive kinase responsible for controlling the cell wall integrity pathway, Slt2. The data indicate that the generation of reactive oxygen species by the electron transport chain is a primary mechanism by which farnesol kills cells. The Pkc1 signaling pathway regulates farnesol-mediated cell death through management of the generation of reactive oxygen species.
AB - The isoprenoid farnesol has been shown to preferentially induce apoptosis in cancerous cells; however, the mode of action of farnesol-induced death is not established. We used chemogenomic profiling using Saccharomyces cerevisiae to probe the core cellular processes targeted by farnesol. This screen revealed 48 genes whose inactivation increased sensitivity to farnesol. The gene set indicated a role for the generation of oxygen radicals by the Rieske iron-sulfur component of complex III of the electron transport chain as a major mediator of farnesol-induced cell death. Consistent with this, loss of mitochondrial DNA, which abolishes electron transport, resulted in robust resistance to farnesol. A genomic interaction map predicted interconnectedness between the Pkc1 signaling pathway and farnesol sensitivity via regulation of the generation of reactive oxygen species. Consistent with this prediction (i) Pkc1, Bck1, and Mkk1 relocalized to the mitochondria upon farnesol addition, (ii) inactivation of the only non-essential and non-redundant member of the Pkc1 signaling pathway, BCK1, resulted in farnesol sensitivity, and (iii) expression of activated alleles of PKC1, BCK1, and MKK1 increased resistance to farnesol and hydrogen peroxide. Sensitivity to farnesol was not affected by the presence of the osmostabilizer sorbitol nor did farnesol affect phosphorylation of the ultimate Pkc1-responsive kinase responsible for controlling the cell wall integrity pathway, Slt2. The data indicate that the generation of reactive oxygen species by the electron transport chain is a primary mechanism by which farnesol kills cells. The Pkc1 signaling pathway regulates farnesol-mediated cell death through management of the generation of reactive oxygen species.
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U2 - 10.1074/jbc.M610575200
DO - 10.1074/jbc.M610575200
M3 - Article
C2 - 17164236
AN - SCOPUS:33947493108
SN - 0021-9258
VL - 282
SP - 4868
EP - 4874
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 7
ER -