ReviewWT1 proteins: functions in growth and differentiation
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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2022, GeneCitation 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).
WT1 regulates HOXB9 gene expression in a bidirectional way
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