Abstract
SummaryThe 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.
Highlights
The Wilms’ tumor suppressor protein WT1 plays a central role in the development of several organs and is mutated or aberrantly expressed in pediatric nephroblastoma
We show that endogenous WT1 in tumor cells is cleaved following cytotoxic drug treatment and demonstrate that this cleavage is HtrA2 dependent
HtrA2 Cleaves WT1 In Vitro We previously mapped the minimal suppression domain of WT1 to a 30 amino acid region juxtaposed to its transcriptional activation domain (McKay et al, 1999; Carpenter et al, 2004)
Summary
The Wilms’ tumor suppressor protein WT1 plays a central role in the development of several organs and is mutated or aberrantly expressed in pediatric nephroblastoma (reviewed in Rivera and Haber, 2005; Hohenstein and Hastie, 2006). WT1 is expressed as four major isoforms that arise from two alternative splice sites. One inserts 3 amino acids (KTS) between zinc fingers 3 and 4 of WT1. This enhances affinity for RNA and is likely to play a posttranscriptional role. The second alternative splice includes a further 17 amino acids (exon 5) within the transactivation domain. WT1 target genes include growth factors, differentiation markers, cell-cycle regulators, and apoptosis regulators (Rae et al, 2004; Renshaw et al, 2004; Kim et al, 2007, 2009)
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