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Oxidant carcinogenesis and antioxidant defense
1Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Epalinges/Lausanne.
Annals of the New York Academy of Sciences
|November 21, 1992
Summary
Oxidants promote cell growth and can trigger reactions similar to growth factors. Cellular antioxidant defenses, like superoxide dismutase (SOD) and catalase (CAT), fine-tune this response, influencing protooncogene expression and cell growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Oxidants promote growth in human and mouse cells, mimicking growth factors.
- Oxidative stress is implicated in inflammation, fibrosis, and tumorigenesis.
- Cellular antioxidant defenses modulate cellular responses to oxidants.
Purpose of the Study:
- To investigate the role of cellular antioxidant defenses in mediating oxidant-induced cell growth.
- To elucidate the molecular mechanisms underlying oxidant-induced protooncogene expression, specifically c-fos.
- To identify key regulatory elements and signaling pathways involved in oxidant-induced gene expression.
Main Methods:
- Cell culture of human and mouse fibroblasts and epidermal cells.
- Genetic manipulation of cells to overproduce superoxide dismutase (SOD) and catalase (CAT).
- Analysis of protooncogene (c-fos, c-myc) induction, DNA damage, and protein kinase activation.
- Identification of DNA regulatory elements (DSE-AP1) and protein factors binding to the c-fos promoter.
- Inhibition studies using protein kinase and ADPR transferase inhibitors.
Main Results:
- Overproduction of SOD sensitized cells to oxidant toxicity, while CAT overproduction conferred protection.
- Overexpression of SOD and CAT diminished oxidant-induced c-fos expression.
- The DSE-AP1 elements in the c-fos 5'-upstream region were identified as critical for oxidant induction.
- Oxidants increased the synthesis of proteins binding to the fos-AP1 enhancer motif.
- Protein phosphorylation and polyADP-ribosylation were found to be essential for c-fos transcriptional induction.
Conclusions:
- A balanced antioxidant defense system is crucial for regulating cellular growth responses to oxidative stress.
- Transcriptional induction of c-fos by oxidants involves specific DNA elements and requires protein kinase and ADPR transferase activity.
- Protein phosphorylation and polyADP-ribosylation are key signaling events in oxidant-mediated c-fos regulation, likely involving FOS and JUN proteins.