WT1 proteins: functions in growth and differentiation

doi:10.1016/S0378-1119(01)00593-5

Gene

Volume 273, Issue 2, 8 August 2001, Pages 141-161

https://doi.org/10.1016/S0378-1119(01)00593-5 Get rights and content

Abstract

The Wilms' tumor 1 gene (WT1) has been identified as a tumor suppressor gene involved in the etiology of Wilms' tumor. Approximately 10% of all Wilms' tumors carry mutations in the WT1 gene. Alterations in the WT1 gene have also been observed in other tumor types, such as leukemia, mesothelioma and desmoplastic small round cell tumor. Dependent on the tumor type, WT1 proteins might either function as tumor suppressor proteins or as survival factors. Mutations in the WT1 gene can also result in congenital abnormalities as observed in Denys–Drash and Frasier syndrome patients. Mouse models have proven the critical importance of WT1 expression for the development of several organs, including the kidneys, the gonads and the spleen. The WT1 proteins seem to perform two main functions. They regulate the transcription of a variety of target genes and may be involved in post-transcriptional processing of RNA. The WT1 gene encodes at least 24 protein forms. These isoforms have partially distinct biological functions and effects, which in many cases are also specific for the model system in which WT1 is studied. This review discusses the molecular mechanisms by which the various WT1 isoforms exert their functions in normal development and how alterations in WT1 may lead to developmental abnormalities and tumor growth.

Introduction

Wilms' tumor or nephroblastoma is a pediatric kidney malignancy that was first described by Max Wilms in 1899. This primitive tumor affects about 1:10,000 children, usually below the age of 5 years, and accounts for approximately 7.5% of all childhood tumors.

Although patients presenting a unilateral tumor can in most cases be successfully treated with chemotherapy and nephrectomy, the biology of Wilms' tumors has for several reasons received a great deal of attention. A major reason is that pediatric tumors often arise through erroneous development and studying these tumors may thus offer insight into embryonic development. Wilms' tumor is thought to arise from mesenchymal blastema cells that fail to differentiate into metanephric structures but continue to proliferate (Hastie, 1994, Machin and McCaughey, 1984). A second reason is that Wilms' tumor is often found in association with other congenital abnormalities, the WAGR (Wilms' tumor, aniridia, genitourinary abnormalities, mental retardation), the Denys–Drash and the Beckwith–Wiedemann syndromes, suggesting an overlap in the pathogenesis of these syndromes and Wilms' tumor (Call et al., 1990, Gessler et al., 1990, Koufos et al., 1989, Pelletier et al., 1991a). Indeed, studies of the WAGR and the Beckwith–Wiedemann syndromes facilitated the mapping of two minimal critical regions on chromosome 11p13 and 11p15, respectively, involved in the development of sporadic Wilms' tumor (Bickmore et al., 1989, Call et al., 1990, Francke et al., 1979, Gessler et al., 1990, Glaser et al., 1989, Koufos et al., 1989, Reeve et al., 1989). Third, a locus for familial Wilms' tumor, which accounts for only 1% of all Wilms' tumors, is not linked to chromosome 11 (Grundy et al., 1988), but instead maps to other chromosomal regions (Rahman et al., 1996, Rahman et al., 1997, Slater and Mannens, 1992), demonstrating that Wilms' tumors are genetically heterogeneous and that at least three candidate genes are implicated in their development.

So far, the Wilms' tumor 1 gene (WT1) at 11p13 is the only gene involved in development of Wilms' tumor that has been cloned (Call et al., 1990, Gessler et al., 1990) and classified as a tumor suppressor gene. It is now recognized that WT1 is homozygously mutated in 5–10% of Wilms' tumors (Gessler et al., 1994, Little and Wells, 1997, Little et al., 1992).

Section snippets

The WT1 gene, mRNAs and proteins

The human WT1 gene spans about 50 kb at chromosome locus 11p13 (Call et al., 1990, Gessler et al., 1990). It comprises ten exons and encodes mRNAs of approximately 3 kb (Call et al., 1990, Gessler et al., 1992).

In mammals, exons 5 and 9 of WT1 are alternatively spliced, giving rise to four different splice isoforms (Fig. 1) (Gessler et al., 1992, Haber et al., 1991). In all other vertebrates tested, exon 5 is not present in the WT1 gene, so that only two different mRNA transcripts are generated

DNA binding and transcription regulation by WT1

As described above, WT1 proteins contain a proline and glutamine-rich region and four contiguous zinc fingers. The presence of these two structural motifs suggested that WT1 is a sequence-specific transcriptional regulator. Therefore, in an initial study to investigate the biochemical activities of WT1, recombinant WT1 protein lacking the KTS insert (WT1−KTS) was used to select specific binding sequences from a pool of degenerate oligonucleotides. The binding sequences obtained were similar to

WT1 as a post-transcriptional regulator

Larsson et al. (1995) have shown that the subnuclear localization of WT1 proteins is splice form-dependent. WT1+KTS isoforms preferentially colocalize with molecules implicated in mRNA splicing to characteristic ‘speckles’. It is now recognized that pre-mRNA splicing is a predominantly cotranscriptional event (Mattaj, 1994) and that the ‘speckles’ may represent storage sites from which splicing factors are recruited to new sites of transcription (Misteli et al., 1997).

More evidence for WT1

WT1 protein partners

In addition to its association with components of the splicing apparatus, WT1 is known to bind to several other proteins (Table 2). In agreement with a role for WT1 in transcriptional regulation, many of these proteins are also transcription factors and/or alter the transcriptional regulatory properties of WT1.

Reddy et al. (1995a) have found that WT1-mediated transcriptional activation is inhibited in a dominant-negative fashion by cotransfection of two WT1 mutants that can not bind to DNA.

WT1 in normal and abnormal development

The cloning of the WT1 gene was facilitated by the mapping of deletions in chromosome 11p13 of patients with the WAGR syndrome (Bickmore et al., 1989, Call et al., 1990, Francke et al., 1979, Gessler et al., 1990, Glaser et al., 1989). Patients affected by this syndrome display congenital developmental abnormalities and sometimes develop Wilms' tumor, suggesting that WT1 is involved in embryonal development. Initial clues to the roles of WT1 during development came from examination of WT1

WT1 in cell culture models of differentiation, apoptosis and tumorigenesis

Wilms' tumors seem to arise from pluripotent blastema cells of the mesenchyme, which do not differentiate properly, but instead continue to proliferate (Hastie, 1994). Furthermore, mutations in WT1 are associated with several developmental abnormality syndromes and gonadoblastoma, indicating that WT1 proteins play an important role in the regulation of growth and differentiation. Therefore, several studies have addressed the involvement of WT1 in these processes by utilizing cell culture model

WT1 in other malignancies than Wilms' tumor

As mentioned previously, WT1 is involved in the development of some gonadoblastomas and leukemias. Furthermore, mutations in the WT1 gene play a role in the development of desmoplastic small round cell tumor (DSRCT) and a small minority of mesotheliomas (Amin et al., 1995, Kumar-Singh et al., 1997, Park et al., 1993a).

Concluding remarks

Since the identification of the WT1 gene it has been clearly proven that the WT1 proteins play an essential role in urogenital development. Still, the exact mechanisms by which the various WT1 isoforms perform their biological functions remain largely unknown. Much of the physiologically relevant information has been obtained from studies on patients suffering from the WAGR, Denys–Drash and FS syndromes, harboring specific types of mutations in the WT1 gene. However, also these studies have not

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Analysis of G-quadruplex forming sequences in podocytes-marker genes and their potential roles in inherited glomerular diseases
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WT1 immunostain is expressed in various benign and malignant neoplasms, as well as normal myoepithelial cells. WT1 shows differential expression in non-neoplastic, benign, and malignant neoplastic myoepithelial cells of the salivary gland. In this study, WT1 immunostain and other myoepithelial markers were compared to investigate the value of WT1 as a myoepithelial marker, and to delineate the expression profile of WT1 in nonsalivary gland myoepithelial cells. WT1, p63, and calponin immunostains were performed on normal and lesional tissues from the breast (adenosis, sclerosing adenosis, lactating adenoma, nipple adenoma, tubular adenoma, adenomyoepithelioma, and adenoid cystic carcinoma [ACC]), skin (cutaneous mixed tumor, hidradenoma, spiradenoma, and ACC), and salivary gland (pleomorphic adenoma and ACC). The stained slides were digitized and orientated with H&E images and assessed simultaneously using QuPath. A total of 129, 58, and 56 breast, cutaneous, and salivary gland lesions, respectively, were included. There was poor agreement between WT1-p63 and WT1-calponin (κ < 0.1) in all organs, with absence of WT1 expression in normal salivary gland myoepithelium and most ACCs. There were no significant differences in WT1 expression in myoepithelial cells in normal breast tissue and benign breast neoplasms. Compared to pleomorphic adenomas, cutaneous mixed tumors showed lower WT1 expression (P < .001). WT1 is a less sensitive myoepithelial marker than calponin and p63. However, its unique pattern of expression in salivary gland primary for pleomorphic adenomas/cutaneous mixed tumor can favor a diagnosis of benign salivary gland tumors, particularly in small biopsy specimens.
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Citation Excerpt :
The results showed that CREB protein expression was suppressed after overexpression of WT1(+KTS) and WT1(-KTS) (Fig. 5B and Fig. 5D), and CREB phosphorylation levels were decreased (Fig. 5B and Fig. 5C). WT1, which encodes a nuclear transcription factor, participates in multiple biological processes, such as gonadal and renal development, cytokine secretion and steroid synthesis (Armstrong et al 1993; Bandiera et al 2015; Cano et al 2013; Kreidberg et al 1993; Scharnhorst et al 2001). Published reports demonstrated that there are only two splicing variants (+KTS or -KTS) in nonmammalian vertebrates(Hastie 2017), and both of them play a pivotal role in tissues or organs, also, the ratio of them is very important and changes in this ratio can cause serious disease(Bandiera et al 2013; Bradford et al 2009; Hammes et al 2001; Ji et al 2013; Miyamoto et al 2008; Wagner et al 2002; Wagner et al 2005; Wells et al 2010).
Multiple Wilms tumor gene 1 (WT1) splicing variants are expressed in mammals, and these variants regulate tumorigenesis and mediate the development of multiple tissues and organs, including gonads. However, WT1 splicing variants (+KTS or -KTS) are expressed in only two nonmammalian vertebrates, and unexpectedly, their functions in chicken ovaries remain elusive. Progesterone (P4) secreted by chicken granulosa cells (GCs) participates in various physiological processes and plays an important role in maintaining reproductive performance. The purpose of this study was to investigate the effect of WT1(+KTS) and WT1(-KTS) on chicken P4 secretion in preovulatory GCs. First, we detected WT1 mRNA expression in GCs from follicles of different developmental stages by Quantitative real-time PCR (RT-qPCR) and found that WT1 mRNA expression was considerably increased in preovulatory GCs compared with prehierarchical GCs. Primary cells collected from preovulatory follicles were treated with WT1(+KTS) or WT1(-KTS) overexpression vectors and subsequently cultured in the absence or presence of follicle-stimulating hormone (FSH). The mRNA levels of FSH-receptor (FSHR) and steroidogenesis genes were determined by RT-qPCR, and the P4 levels in the cell supernatants were measured by radioimmunoassay (RIA). Both WT1(+KTS) and WT1(-KTS) significantly decreased P4 secretion due to a reduction in FSHR, STAR and CYP11A1 mRNA levels. Western blotting revealed that ERK1/2 and BRAF phosphorylation levels were suppressed after overexpression of WT1(+KTS) or WT1(-KTS), whereas total protein and mRNA levels were not significantly changed. In addition, CREB protein and phosphorylation levels were inhibited after overexpression of WT1(+KTS) or WT1(-KTS). In conclusion, WT1(+KTS) and WT1(-KTS) inhibited CREB protein activity and significantly reduced FSHR, STAR and CYP11A1 mRNA levels, which subsequently suppressed FSH-induced P4 secretion in preovulatory GCs by modulating ERK1/2 signaling.
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The homeoboxB9 (HOXB9) gene is necessary for specification of the anterior-posterior body axis during embryonic development and expressed in various types of cancer.
Here we show that the Wilms tumor transcription factor WT1 regulates the HOXB9 gene in a bidirectional manner. Silencing of WT1 activates HOXB9 in Wt1 expressing renal cell adenocarcinoma-derived 786-0 cells, mesonephric M15 cells and ex vivo cultured murine embryonic kidneys. In contrast, HOXB9 expression in U2OS osteosarcoma and human embryonic kidney (HEK) 293 cells, which lack endogenous WT1, is enhanced by overexpression of WT1. Consistently, Hoxb9 promoter activity is stimulated by WT1 in transiently transfected U2OS and HEK293 cells, but inhibited in M15 cells with CRISPR/Cas9-mediated Wt1 deletion. Electrophoretic mobility shift assay and chromatin immunoprecipitation demonstrate binding of WT1 to the HOXB9 promoter in WT1-overexpressing U2OS cells and M15 cells. BASP1, a transcriptional co-repressor of WT1, is associated with the HOXB9 promoter in the chromatin of these cell lines. Co-transfection of U2OS and HEK293 cells with BASP1 plus WT1 prevents the stimulatory effect of WT1 on the HOXB9 promoter.
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ReviewWT1 proteins: functions in growth and differentiation

Abstract

Introduction

Section snippets

The WT1 gene, mRNAs and proteins

DNA binding and transcription regulation by WT1

WT1 as a post-transcriptional regulator

WT1 protein partners

WT1 in normal and abnormal development

WT1 in cell culture models of differentiation, apoptosis and tumorigenesis

WT1 in other malignancies than Wilms' tumor

Concluding remarks

Genomics

J. Biol. Chem.

FEBS Lett.

Cell

Leuk. Res.

Mol. Diagn.

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

J. Biol. Chem.

Blood

J. Biol. Chem.

Genomics

Genomics

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Blood

Blood

J. Pediatr.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Blood

Blood

Cell

J. Biol. Chem.

Cell

Cell

Biochem. Biophys. Res. Commun.

Midkine as a novel target gene for the Wilms' tumor suppressor gene (WT1)

Oncogene

A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines

Oncogene

Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma

Am. J. Pathol.

The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo

Mech. Dev.

Identification of mutations in the WT1 gene in tumours from patients with the WAGR syndrome

Oncogene

Donor splice-site mutations in WT1 are responsible for Frasier syndrome

Nat. Genet.

The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor

Hum. Mutat.

WT1 splicing alterations in Wilms' tumors

Clin. Cancer Res.

Modulation of DNA binding specificity by alternative splicing of the Wilms' tumor WT1 gene transcript

Science

Inactivation of the remaining allele of the WT1 gene in a Wilms' tumour from a WAGR patient

Oncogene

RNA binding by the Wilms' tumor suppressor zinc finger proteins

Proc. Natl. Acad. Sci. USA

Transcriptional activation of the syndecan-1 promoter by the Wilms' tumor protein WT1

Oncogene

WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes

Genes Dev.

PAX8-mediated activation of the WT1 tumor suppressor gene

EMBO J.

The paired-box transcription factor, PAX2, positively modulates expression of the Wilms' tumor suppressor gene (WT1)

Oncogene

The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun

Oncogene

Review
WT1 proteins: functions in growth and differentiation