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Activation of the c-jun protooncogene in human myeloid leukemia cells treated with etoposide
E Rubin1, S Kharbanda, H Gunji
1Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Abstract:
The epipodophyllotoxin etoposide is an inhibitor of topoisomerase II. The effects of this agent on gene expression, particularly the transcriptional induction of genes implicated in growth control, are unknown. The present results demonstrate that etoposide induces expression of the c-jun protooncogene in HL-60 myeloid leukemia cells. This induction of c-jun expression was maximal at 3 hr and was transient. Similar findings were obtained in the human U-937 myeloid leukemia cell line. Nuclear run-on assays demonstrated that the induction of c-jun expression by etoposide is regulated at the transcriptional level. The results further demonstrate that etoposide-induced c-jun expression occurs in association with the appearance of c-fos transcripts. Moreover, the c-jun gene is induced by etoposide during periods of oligonucleosomal DNA cleavage, which is characteristic of programmed cell death. These findings suggest that transcriptional induction of c-jun expression represents a signaling pathway activated in the cellular response to etoposide-induced DNA damage.
Insights
Etoposide, a topoisomerase II inhibitor, transiently induces c-jun protooncogene expression in leukemia cells. This transcriptional induction occurs with DNA damage, suggesting a role in cellular response.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Signaling
Background:
- Etoposide is a topoisomerase II inhibitor used in cancer therapy.
- Its effects on gene expression, particularly growth control genes, are not fully understood.
Purpose of the Study:
- To investigate the impact of etoposide on gene expression, specifically the c-jun protooncogene.
- To determine the regulatory mechanisms and cellular context of etoposide-induced gene expression.
Main Methods:
- Utilized HL-60 and U-937 myeloid leukemia cell lines.
- Employed nuclear run-on assays to assess transcriptional regulation.
- Monitored gene expression and DNA cleavage patterns.
Main Results:
- Etoposide induced transient, time-dependent expression of the c-jun protooncogene in both cell lines.
- Transcriptional regulation was confirmed via nuclear run-on assays.
- Etoposide-induced c-jun expression correlated with c-fos transcript appearance and DNA cleavage characteristic of programmed cell death.
Conclusions:
- Transcriptional induction of c-jun is a key cellular response to etoposide-induced DNA damage.
- This pathway may involve c-fos and is linked to programmed cell death.
- Etoposide's effects on gene expression provide insights into its mechanism of action in leukemia treatment.