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A Role for Protein Kinase C- in the Regulation of Ornithine Decarboxylase Expression by Oxidative Stress¹

Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205

The expression of genes that regulate cell growth, such as ornithine decarboxylase (ODC), can be modulated by oxidant tumor promoters. Treatment of murine papilloma PE cells with H₂O₂ led to a transient induction of ODC enzyme activity, which could be blocked by calphostin, a nonspecific inhibitor of protein kinase C (PKC). Peak activity (11-fold) occurred 5–6 h after treatment, followed by a rapid decline. The increase in ODC activity was associated with an elevation of both ODC mRNA (3-fold) and protein (7-fold). Direct involvement of PKC in the regulation of ODC by oxidants was determined by stable transfection of PE cells with a dominant-negative PKC- mutant. PKC- activity was completely inhibited in response to H₂O₂ in cells overexpressing mutant PKC- compared with cells transfected with a blank plasmid. Induction of ODC mRNA, protein, and activity was also completely inhibited in cells expressing the PKC- mutant after H₂O₂ treatment. Activation of an ODC promoter-luciferase reporter construct by H₂O₂ was attenuated in mutant cells compared with control cells, further confirming that ODC is regulated transcriptionally by PKC-. However, fold-increases in ODC mRNA and protein were much less than the increase in activity, suggesting that ODC may also undergo posttranscriptional regulation in the presence of oxidants. Taken together, these studies provide new insight into the regulation of ODC by oxidants and suggest that PKC- may play a critical role in this regulation.

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