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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Identification of Tcf-4 as a transcriptional target of p53 signalling
Karen Rother1, Cindy Johne, Katja Spiesbach
1Medizinische Klinik und Poliklinik II, Max-Bürger-Forschungszentrum, Universität Leipzig, Johannisallee 30, Leipzig D-04103, Germany.
Abstract:
T-cell factor (Tcf)-4 is a main transcription factor to pass on Wnt/beta-catenin signalling. The tumour suppressor protein p53 contributes as a transcription factor to cell-cycle arrest and apoptosis induction. Mutations of components in p53 and Wnt/beta-catenin signalling networks play a part in tumour formation. Here, we identify the Tcf-4 gene as a downstream effector of p53. Induction of wild-type p53 in a tet-off regulated human colon cell system leads to the reduction of Tcf-4 mRNA and protein levels. Also, mRNA of the Tcf-4 target gene uPAR is downregulated after p53 induction. Expression of a luciferase reporter controlled by the Tcf-4 promoter is repressed by wild-type p53, but not by a p53 mutant deficient in DNA binding. Such a regulation is seen in cell lines of different origin. These findings directly link Wnt/beta-catenin signalling and p53 tumour suppressor function and may provide a mechanism by which loss of p53 function contributes to progression in the adenoma/carcinoma sequence in colon tumours. Furthermore, since Tcf-4 is expressed in many tissues and downregulation of Tcf-4 by p53 is seen in several different cell types, this regulation likely plays a role in proliferation control of all tissues that can express p53 and Tcf-4.
Insights
The tumor suppressor p53 directly regulates T-cell factor (Tcf)-4, a key Wnt/beta-catenin signaling component. This finding links p53 function to colon tumor progression and proliferation control.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- T-cell factor (Tcf)-4 is a key transcription factor in Wnt/beta-catenin signaling.
- The tumor suppressor p53 induces cell-cycle arrest and apoptosis.
- Mutations in p53 and Wnt/beta-catenin pathways are implicated in tumorigenesis.
Purpose of the Study:
- To investigate the relationship between p53 and Tcf-4.
- To determine if p53 regulates Tcf-4 expression.
- To elucidate the role of this interaction in colon cancer progression.
Main Methods:
- Utilized a tet-off regulated human colon cell system to induce wild-type p53.
- Measured Tcf-4 mRNA and protein levels post-p53 induction.
- Assessed Tcf-4 promoter activity using a luciferase reporter assay with wild-type and mutant p53.
Main Results:
- Wild-type p53 induction reduced Tcf-4 mRNA and protein levels.
- Tcf-4 target gene uPAR mRNA was downregulated following p53 induction.
- Wild-type p53 repressed Tcf-4 promoter activity, while a DNA-binding deficient p53 mutant did not.
Conclusions:
- Identified Tcf-4 as a direct downstream target of p53.
- Established a molecular link between p53 tumor suppressor function and Wnt/beta-catenin signaling.
- Proposed a mechanism for p53 loss contributing to colon adenoma/carcinoma progression and highlighted the role in proliferation control across tissues.
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