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WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis
C Englert1, X Hou, S Maheswaran
1Laboratory of Molecular Genetics, Massachusetts General Hospital Cancer Center, Charlestown 02129, USA.
Abstract:
The Wilms tumor suppressor gene WT1 encodes a developmentally regulated transcription factor that is mutated in a subset of embryonal tumors. To test its functional properties, we developed osteosarcoma cell lines expressing WT1 under an inducible tetracycline-regulated promoter. Induction of WT1 resulted in programmed cell death. This effect, which was differentially mediated by the alternative splicing variants of WT1, was independent of p53. WT1-mediated apoptosis was associated with reduced synthesis of the epidermal growth factor receptor (EGFR), but not of other postulated WT1-target genes, and it was abrogated by constitutive expression of EGFR. WT1 repressed transcription from the EGFR promoter, binding to two TC-rich repeat sequences. In the developing kidney, EGFR expression in renal precursor cells declined with the onset of WT1 expression. Repression of EGFR and induction of apoptosis by mechanism that may contribute to its critical role in normal kidney development and to the immortalization of tumor cells with inactivated WT1 alleles.
Insights
The Wilms tumor suppressor gene (WT1) induces cancer cell death by repressing epidermal growth factor receptor (EGFR) synthesis. This finding reveals a novel mechanism for WT1
Area of Science:
- Oncology
- Molecular Biology
- Developmental Biology
Background:
- The Wilms tumor suppressor gene WT1 is crucial for kidney development and is frequently mutated in embryonal tumors.
- WT1 encodes a transcription factor regulating gene expression during development.
- Understanding WT1's function is key to comprehending tumor development and potential therapeutic strategies.
Purpose of the Study:
- To investigate the functional properties of the WT1 gene.
- To elucidate the mechanism by which WT1 influences cell death.
- To determine the role of WT1 in regulating epidermal growth factor receptor (EGFR) expression.
Main Methods:
- Development of osteosarcoma cell lines with inducible WT1 expression using a tetracycline-regulated promoter.
- Analysis of WT1-induced programmed cell death and its independence from p53.
- Assessment of WT1's effect on the synthesis of EGFR and other potential target genes.
- Investigation of WT1's direct transcriptional repression of the EGFR promoter.
Main Results:
- Induction of WT1 triggered programmed cell death (apoptosis) in osteosarcoma cells.
- WT1-mediated apoptosis was linked to decreased epidermal growth factor receptor (EGFR) synthesis.
- WT1 directly repressed transcription from the EGFR promoter by binding to specific DNA sequences.
- EGFR expression decreased in developing kidney precursor cells as WT1 expression initiated.
Conclusions:
- WT1 induces apoptosis, partly through the repression of EGFR, highlighting a novel mechanism.
- This WT1-EGFR regulatory pathway is critical for normal kidney development.
- Inactivation of WT1 in tumors may lead to uncontrolled EGFR signaling and cell immortalization.