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Published on: August 19, 2014
p300/CBP-dependent and -independent transcriptional interference between NF-kappaB RelA and p53
1Department of Molecular Pathology, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-0934, Japan.
Abstract:
p53 and NF-kappaB RelA are activated by various genotoxic agents and mutually suppress each other's ability to activate transcription, most likely through competition for transcriptional coactivators such as CBP or p300. However, we found that the inhibition by RelA of p53 transcriptional activity is not completely restored by CBP/p300 overexpression and that a p53 mutant can not suppress RelA activity despite of its ability to bind CBP/p300. In the present study, we further present evidence that these two transcriptional factors directly interact both in vivo and in vitro. These results therefore indicate that the cross transcriptional interference between p53 and RelA is partly caused by the direct interaction between these two transcription factors which is mediated by their dimerization/tetramerization domains and results in inhibition of each other's transcriptional activity. Finally, cells derived from RelA knockout mice showed enhanced p53 transcriptional activity, suggesting that this cross transcriptional interference is physiologically important in cellular response to genotoxic stress.
Insights
The tumor suppressor p53 and transcription factor NF-kappaB RelA directly interact, inhibiting each other's activity. This interaction is crucial for cellular responses to genotoxic stress.
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- p53 and NF-kappaB RelA are activated by genotoxic agents.
- These factors mutually suppress transcriptional activity, potentially via coactivator competition (CBP/p300).
- Previous findings suggested incomplete restoration of p53 activity by coactivator overexpression and a p53 mutant's inability to suppress RelA.
Purpose of the Study:
- To investigate the mechanism of mutual transcriptional suppression between p53 and NF-kappaB RelA.
- To determine if direct interaction occurs between p53 and RelA.
- To assess the physiological importance of this interaction in genotoxic stress response.
Main Methods:
- In vivo and in vitro interaction assays.
- Analysis of transcriptional activity in RelA knockout mouse cells.
- Mutational analysis of p53 interaction domains.
Main Results:
- p53 and RelA were found to directly interact both in vivo and in vitro.
- Direct interaction is mediated by their dimerization/tetramerization domains.
- Cells lacking RelA exhibited enhanced p53 transcriptional activity.
Conclusions:
- Direct physical interaction between p53 and RelA contributes to their mutual transcriptional inhibition.
- This interaction, mediated by specific domains, plays a significant physiological role in cellular responses to genotoxic stress.
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