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Rapid and preferential activation of the c-jun gene during the mammalian UV response
Y Devary1, R A Gottlieb, L F Lau
1Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla 92093.
Abstract:
Exposure of mammalian cells to DNA-damaging agents leads to activation of a genetic response known as the UV response. Because several previously identified UV-inducible genes contain AP-1 binding sites within their promoters, we investigated the induction of AP-1 activity by DNA-damaging agents. We found that expression of both c-jun and c-fos, which encode proteins that participate in formation of the AP-1 complex, is rapidly induced by two different DNA-damaging agents: UV and H2O2. Interestingly, the c-jun gene is far more responsive to UV than any other immediate-early gene that was examined, including c-fos. Other jun and fos genes were only marginally affected by UV or H2O2. Furthermore, UV is a much more efficient inducer of c-jun than phorbol esters, the standard inducers of c-jun expression. This preferential response of the c-jun gene is mediated by its 5' control region and requires the TPA response element, suggesting that this element also serves as an early target for the signal transduction pathway elicited by DNA damage. Both UV and H2O2 lead to a long-lasting increase in AP-1 binding activity, suggesting that AP-1 may mediate the induction of other damage-inducible genes such as human collagenase.
Insights
DNA-damaging agents like UV and H2O2 rapidly activate the AP-1 complex by inducing c-jun gene expression. This response, crucial for the UV response, is mediated by the TPA response element in the c-jun promoter.
Area of Science:
- Molecular Biology
- Genetics
- Cellular Response
Background:
- Mammalian cells activate a genetic response, the UV response, upon exposure to DNA-damaging agents.
- Several UV-inducible genes possess AP-1 binding sites in their promoters, suggesting a role for AP-1 in this response.
Purpose of the Study:
- To investigate the induction of Activator Protein-1 (AP-1) activity by DNA-damaging agents.
- To determine the specific jun and fos gene responses to UV and hydrogen peroxide (H2O2).
Main Methods:
- Exposure of mammalian cells to UV and H2O2.
- Analysis of c-jun and c-fos gene expression.
- Investigation of AP-1 binding activity.
- Examination of the role of the 5' control region and TPA response element in c-jun induction.
Main Results:
- Both UV and H2O2 rapidly induce the expression of c-jun and c-fos, key components of the AP-1 complex.
- The c-jun gene shows significantly higher responsiveness to UV compared to other examined immediate-early genes, including c-fos.
- UV is a more potent inducer of c-jun than standard inducers like phorbol esters.
- A long-lasting increase in AP-1 binding activity is observed following exposure to both UV and H2O2.
Conclusions:
- The c-jun gene is a primary target of DNA-damaging agents, exhibiting preferential induction.
- The TPA response element within the c-jun 5' control region is likely an early target in the DNA damage signal transduction pathway.
- AP-1 activation by DNA damage may mediate the induction of other damage-inducible genes, such as human collagenase.