A role for c-myc in chemically induced renal-cell death.
A variety of genes, including c-myc, are activated by chemical toxicants in vivo and in vitro. Although enforced c-myc expression induces apoptosis after withdrawing survival factors, it is not clear if activation of the endogenous c-myc gene is an apoptotic signal after toxicant exposure. The renal tubular epithelium is a target for many toxicants. c-myc expression is activated by tubular damage. In quiescent LLC-PK1 renal epithelial cells, c-myc but not max or mad mRNA is induced by the nephrotoxicant S-(1,2-dichlorovinyl)-L-cysteine (DCVC). The kinetics of DCVC-induced c-myc expression and apoptosis suggested an association between cell death and prolonged activation of c-myc expression after toxicant exposure. Accordingly, prolonged activation of an estrogen receptor-Myc fusion construct, but not a construct in which a c-Myc transactivation domain had been deleted, was sufficient to induce apoptosis in LLC-PK1 cells. Moreover, under conditions in which necrosis was the predominant cell death pathway caused by DCVC in parental cells, overexpressing c-myc biased the cell death pathway toward apoptosis. DCVC also induced ornithine decarboxylase (odc) mRNA and activated the odc promoter. Activation of the odc promoter by DCVC required consensus c-Myc-Max binding sites in odc intron 1. Inhibiting ODC activity with alpha-difluoromethylornithine delayed DCVC-induced cell death. Therefore, odc is a target gene in the DCVC apoptotic pathway involving c-myc activation and contributes to apoptosis. Finally, a structurally related cytotoxic but nongenotoxic analog of DCVC did not induce c-myc and did not activate the odc promoter or induce apoptosis. The data support the hypothesis that activation of apoptotic cell death in quiescent renal epithelial cells involves induction of c-myc. This is the first study to demonstrate that c-myc induction by a specific nephrotoxicant leads to gene activation and cell death.
Zhan
Y
Y
W. Alton Jones Cell Science Center, Lake Placid, New York 12946, USA.
Cleveland
J L
JL
Stevens
J L
JL
D017209:Apoptosis; D016923:Cell Death; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects*; D007700:Kinetics; D009336:Necrosis; D009955:Ornithine Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D016271:Proto-Oncogene Proteins c-myc; C039961:S-(1,2-dichlorovinyl)cysteine; D009955:Ornithine Decarboxylase; D003545:Cysteine