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A role for c-myc in chemically induced renal-cell death

Academic Article
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Overview

authors

  • Zhan, Y.
  • Cleveland, John
  • Stevens, J. L.

publication date

  • 1997

journal

  • Molecular and Cellular Biology  Journal

abstract

  • 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.

subject areas

  • Apoptosis
  • Cell Death
  • Cells, Cultured
  • Cysteine
  • Epithelial Cells
  • Gene Expression Regulation
  • Kidney Tubules
  • Kinetics
  • Necrosis
  • Ornithine Decarboxylase
  • Proto-Oncogene Proteins c-myc
  • Regulatory Sequences, Nucleic Acid
  • Transcription, Genetic
  • Transcriptional Activation
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Identity

PubMed Central ID

  • PMC232530

International Standard Serial Number (ISSN)

  • 0270-7306

PubMed ID

  • 9343440
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Additional Document Info

start page

  • 6755

end page

  • 6764

volume

  • 17

issue

  • 11

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