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Induction of p21 by the Wilms' tumor suppressor gene WT1
C Englert1, S Maheswaran, A J Garvin
1Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown 02129, USA.
Abstract:
WT1 encodes a zinc finger transcription factor that is expressed in the developing kidney and the inactivation of which leads to Wilms' tumor, a pediatric kidney cancer. We have recently shown that inducible expression of WT1 in osteosarcoma cells triggers programmed cell death, an effect that is associated with transcriptional repression of the endogenous epidermal growth factor receptor. We now show that WT1-mediated apoptosis is preceded by induction of the cyclin-dependent kinase inhibitor p21, associated with G1 phase arrest. This effect is only demonstrated by WT1 isoforms with an intact DNA binding domain, and it is associated with increased expression of endogenous p21 mRNA. WT1-mediated induction of p21 is independent of p53, another tumor suppressor gene known to regulate p21 expression. In the kidney, p21 is expressed in differentiating glomerular podocytes along with WT1. We conclude that induction of p21 expression may contribute to WT1-dependent differentiation pathways in the kidney and potentially to the function of WT1 as a tumor suppressor gene.
Insights
Wilms tumor gene WT1 induces programmed cell death by increasing p21 expression, independent of p53. This suggests WT1
Area of Science:
- Molecular Biology
- Cancer Research
- Developmental Biology
Background:
- WT1 (Wilms tumor gene 1) is a transcription factor crucial for kidney development and acts as a tumor suppressor.
- WT1 inactivation is linked to Wilms tumor, a pediatric kidney cancer.
- Previous studies showed WT1 induces apoptosis in osteosarcoma cells via epidermal growth factor receptor repression.
Purpose of the Study:
- To investigate the molecular mechanisms underlying WT1-mediated apoptosis.
- To determine the role of p21 in WT1-induced cell death.
- To explore the relationship between WT1, p21, and kidney development.
Main Methods:
- Inducible WT1 expression in osteosarcoma cells.
- Cell cycle analysis (G1 phase arrest).
- Analysis of p21 mRNA and protein expression.
- Assessment of WT1 isoforms with intact DNA binding domains.
- Comparison with p53-dependent pathways.
Main Results:
- WT1-mediated apoptosis is preceded by induction of p21 (cyclin-dependent kinase inhibitor).
- WT1 induces G1 phase arrest and increases p21 mRNA expression.
- This effect requires an intact WT1 DNA binding domain.
- WT1-induced p21 expression is independent of the p53 tumor suppressor gene.
- WT1 and p21 are co-expressed in differentiating glomerular podocytes.
Conclusions:
- WT1 induces apoptosis and cell cycle arrest through p21.
- WT1's tumor suppressor function may involve p21 induction.
- WT1-p21 pathway may contribute to kidney differentiation processes.