HtrA2, taming the oncogenic activities of WT1

Abstract

Wilms' tumour is a paediatric malignancy of the kidneys and is one of the most common solid childhood cancers. The Wilms' tumour 1 protein (WT1) is a transcription factor that can either activate or repress genes involved in growth, apoptosis and differentiation. It is frequently mutated or aberrantly expressed in Wilms' tumour, where the wild type protein would normally act as a tumour suppressor. Several studies, however, have found that wild type WT1 acts as an oncogene in adult tumours, primarily through the inhibition of apoptosis. The expression of WT1 correlates with the aggressiveness of several adult cancers, and its continued expression following treatment is indicative of a poor outcome.We recently found that the treatment of tumour cell lines with cytotoxic drugs leads to the cleavage of WT1 by the serine protease HtrA2. HtrA2 binds to a specific region of WT1, the suppression domain, and then cleaves WT1 at multiple sites. The HtrA2-mediated proteolysis of WT1 leads to its removal from gene promoter regions and changes in gene expression. Cleavage of WT1 by HtrA2 enhances apoptosis. This event is advantageous to the treatment of adult tumours where WT1 acts as an oncogene. However, when WT1 is acting as a tumour suppressor in paediatric malignancies, proteolysis by HtrA2 would be antagonistic to therapy.

Figure 1

Cytotoxic drugs stimulate the processing of WT1 by HtrA2. HtrA2 (H) is present in the mitochondria and nucleus. Upon exposure to apoptotic agents, HtrA2 cleaves WT1 (W), resulting in its loss from gene promoters, with concomitant changes in the expression of these genes. Those genes that were subject to repression or activation by WT1 would be upregulated and downregulated respectively. The HtrA2-dependent proteolysis of WT1 acts to drive apoptosis.

Figure 2

Functional motifs and interactions of WT1. A linear schematic of WT1 is shown with numbering indicating amino acids. Zn is zinc finger, A is the activation domain, R is the repression domain, SD is the suppression domain. The alternative splice sites (17AA and KTS) are indicated. The HtrA2 cleavage sites, the self-association, nuclear export and nucleic acid-binding domains are indicated below and post-translational modifications (sumoylation and phosphorylation) are shown above. The binding sites in WT1 for BASP1, HtrA2, Hsp70, Par-4 and p53 are indicated.