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Physical and functional interaction between WT1 and p53 proteins
S Maheswaran1, S Park, A Bernard
1Massachusetts General Hospital Cancer Center, Charlestown.
Abstract:
WT1 is a tumor-suppressor gene expressed in the developing kidney, whose inactivation leads to the development of Wilms tumor, a pediatric kidney cancer. WT1 encodes a transcription factor which binds to the EGR1 consensus sequence, mediating transcriptional repression. We now demonstrate that p53, the product of a tumor-suppressor gene with ubiquitous expression, physically associates with WT1 in transfected cells. The interaction between WT1 and p53 modulates their ability to transactivate their respective targets. In the absence of p53, WT1 acts as a potent transcriptional activator of the early growth response gene 1 (EGR1) site, rather than a transcriptional repressor. In contrast, WT1 exerts a cooperative effect on p53, enhancing its ability to transactivate the muscle creatine kinase promoter.
Insights
The Wilms tumor suppressor WT1 protein physically interacts with p53. This interaction alters their functions, with WT1 activating EGR1 without p53, and cooperating with p53 on other targets.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Developmental Biology
Background:
- Wilms tumor (WT) is a pediatric kidney cancer linked to the WT1 tumor suppressor gene.
- WT1 encodes a transcription factor regulating gene expression.
- p53 is a critical tumor suppressor with widespread expression.
Purpose of the Study:
- To investigate the physical interaction between WT1 and p53.
- To determine how this interaction affects their transcriptional activities.
Main Methods:
- Transfection of cells to express WT1 and p53.
- Co-immunoprecipitation to assess physical association.
- Reporter gene assays to measure transcriptional activity.
Main Results:
- WT1 and p53 physically associate in transfected cells.
- In the absence of p53, WT1 activates transcription of the EGR1 site.
- WT1 enhances p53's transactivation of the muscle creatine kinase promoter.
Conclusions:
- WT1 and p53 interaction modulates their distinct transcriptional functions.
- WT1's role shifts from repressor to activator depending on p53 presence.
- This interplay is crucial for understanding WT1's tumor-suppressive mechanisms.