Mechanisms of transcriptional regulation by WT1 (Wilms' tumour 1)

Abstract

The WT1 (Wilms' tumour 1) gene encodes a zinc finger transcription factor and RNA-binding protein that direct the development of several organs and tissues. WT1 manifests both tumour suppressor and oncogenic activities, but the reasons behind these opposing functions are still not clear. As a transcriptional regulator, WT1 can either activate or repress numerous target genes resulting in disparate biological effects such as growth, differentiation and apoptosis. The complex nature of WT1 is exemplified by a plethora of isoforms, post-translational modifications and multiple binding partners. How WT1 achieves specificity to regulate a large number of target genes involved in diverse physiological processes is the focus of the present review. We discuss the wealth of the growing molecular information that defines our current understanding of the versatility and utility of WT1 as a master regulator of organ development, a tumour suppressor and an oncogene.

Figure 1. Functional motifs of the Wilms’ tumour 1 protein WT1

A linear schematic is shown with numbering indicating the amino acids. The alternative splice sites (17AA and KTS) are shown above along with the post-translational modifications (SUMOylation and phosphorylation). Regions of the protein involved in self-association, nuclear export and nuclear acid binding are shown above. The binding sites of some of WT1 cofactors, such as BASP1, HtrA2, WTX, STAT3, p53, Par-4, CBP and SRY, are indicated below the schematic diagram. Lightning bolts indicate HtrA2 cleavage sites in WT1. A, activation domain; R, repression domain; Zn, zinc finger.

Figure 2. DNA-binding transcription factors that associate with WT1

Mechanisms of action of complexes formed by DNA-binding transcription factors and WT1 are shown. The cofactors lead to either gene activation (left-hand panels) or repression (right-hand panels) by WT1. The small yellow circle in (I) indicates that the interaction is dependent on the splice isoform of WT1.

Figure 3. Transcriptional co-regulators of WT1

Transcriptional regulation by WT1 and its transcriptional cofactors are shown, leading to the formation of either an activator complex (left-hand panels) or a repressor complex (right-hand panels). The small yellow circle in (C) indicates that the interaction is dependent on the splice isoform of WT1. Histone modifications are indicated (Ac; H3K27me3).