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Published on: July 14, 2016
The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi
Jörg Hartkamp1, Brian Carpenter, Stefan G E Roberts
1Faculty of Life Sciences, The Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Abstract:
The Wilms' tumor suppressor protein WT1 functions as a transcriptional regulator of genes controlling growth, apoptosis, and differentiation. It has become clear that WT1 can act as an oncogene in many tumors, primarily through the inhibition of apoptosis. Here, we identify the serine protease HtrA2 as a WT1 binding partner and find that it cleaves WT1 at multiple sites following the treatment of cells with cytotoxic drugs. Ablation of HtrA2 activity either by chemical inhibitor or by siRNA prevents the proteolysis of WT1 under apoptotic conditions. Moreover, the apoptosis-dependent cleavage of WT1 is defective in HtrA2 knockout cells. Proteolysis of WT1 by HtrA2 causes the removal of WT1 from its binding sites at gene promoters, leading to alterations in gene regulation that enhance apoptosis. Our findings provide insights into the function of HtrA2 in the regulation of apoptosis and the oncogenic activities of WT1.
Insights
The serine protease HtrA2 cleaves the Wilms
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Death Pathways
Background:
- The Wilms' tumor suppressor protein WT1 is a transcriptional regulator involved in cell growth, apoptosis, and differentiation.
- WT1 can function as an oncogene in various tumors, often by inhibiting apoptosis.
- Understanding WT1 regulation is crucial for cancer therapy development.
Purpose of the Study:
- To identify novel binding partners of WT1.
- To investigate the role of HtrA2 in WT1 regulation during apoptosis.
- To elucidate the mechanism by which HtrA2 influences WT1's oncogenic activity.
Main Methods:
- Identification of HtrA2 as a WT1 binding partner.
- Assessment of WT1 cleavage by HtrA2 using chemical inhibitors and siRNA.
- Analysis of WT1 proteolysis in HtrA2 knockout cells.
- Chromatin immunoprecipitation to determine WT1 binding to gene promoters.
Main Results:
- HtrA2 directly cleaves WT1 at multiple sites upon cytotoxic drug treatment.
- Inhibition or ablation of HtrA2 prevents WT1 proteolysis during apoptosis.
- HtrA2-mediated cleavage of WT1 leads to its dissociation from gene promoters, enhancing apoptosis.
- This process is impaired in HtrA2 knockout cells.
Conclusions:
- HtrA2 is a key regulator of WT1 stability and function during apoptosis.
- HtrA2-mediated cleavage of WT1 modulates gene expression to promote cell death.
- These findings reveal a novel mechanism controlling WT1's oncogenic potential and offer insights into apoptosis regulation.
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