WT1 proteins : functions in growth and differentiation Citation for published version (APA): Scharnhorst, V., Eb, van der, A. J., & Jochemsen, A. G. (2001). WT1 proteins : functions in growth and differentiation. Gene, 273(2), 141-161. https://doi.org/10.1016/S0378-1119(01)00593-5 DOI: 10.1016/S0378-1119(01)00593-5 Document status and date: Published: 01/01/2001 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 29. Sep. 2021 Gene 273 ,2001) 141±161 www.elsevier.com/locate/gene Review WT1 proteins: functions in growth and differentiation Volkher Scharnhorst, Alex J. van der Eb, Aart G. Jochemsen* Department of Molecular and Cellular Biology and Center for Biomedical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands Received 23 March 2001; received in revised form 11 June 2001; accepted 2 July 2001 Received by A.J. van Wijnen Abstract The Wilms' tumor 1 gene ,WT1) has been identi®ed 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 speci®c 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. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Wilms' tumor 1 protein; Tumor suppressor; Transcriptional regulation; Splicing factors; Differentiation 1. Introduction nephrectomy, the biology of Wilms' tumors has for several reasons received a great deal of attention. A major reason is Wilms' tumor or nephroblastoma is a pediatric kidney that pediatric tumors often arise through erroneous develop- malignancy that was ®rst described by Max Wilms in ment and studying these tumors may thus offer insight into 1899. This primitive tumor affects about 1:10,000 children, embryonic development. Wilms' tumor is thought to arise usually below the age of 5 years, and accounts for approxi- from mesenchymal blastema cells that fail to differentiate mately 7.5% of all childhood tumors. into metanephric structures but continue to proliferate Although patients presenting a unilateral tumor can in ,Hastie, 1994; Machin and McCaughey, 1984). A second most cases be successfully treated with chemotherapy and reason is that Wilms' tumor is often found in association with other congenital abnormalities, the WAGR ,Wilms' tumor, aniridia, genitourinary abnormalities, mental retar- Abbreviations: AdBRK cells, adenovirus-transformed baby rat kidney dation), the Denys±Drash and the Beckwith±Wiedemann cells; CSF-I, colony stimulating factor I; CTGF, connective tissue growth syndromes, suggesting an overlap in the pathogenesis of factor; Cu,Zn-SOD, Cu,Zn-superoxide dismutase; DDS, Denys±Drash syndrome; DSRCT, desmoplastic small round cell tumor; EGF, epidermal these syndromes and Wilms' tumor ,Call et al., 1990; Gess- growth factor; EGFR, epidermal growth factor receptor; FS, Frasier ler et al., 1990; Koufos et al., 1989; Pelletier et al., 1991a). syndrome; IGF-II, insulin-like growth factor-II; IGF-IR, insulin-like Indeed, studies of the WAGR and the Beckwith±Wiede- growth factor-I receptor; MDR-1, multidrug resistance-1; MIS, MuÈllerian mann syndromes facilitated the mapping of two minimal inhibitory substance; ODC, ornithine decarboxylase; PDGF-A, platelet- critical regions on chromosome 11p13 and 11p15, respec- derived growth factor-A chain; PKA, protein kinase A; PKC, protein kinase C; RAR-a, retinoic acid receptor-a; SF-1, steroidogenic factor-1; TGF-b, tively, involved in the development of sporadic Wilms' transforming growth factor-b; TPA, 12-O-tetradecanoylphorbol-13-acet- tumor ,Bickmore et al., 1989; Call et al., 1990; Francke et ate; WAGR, Wilms' tumor, aniridia, genitourinary abnormalities and al., 1979; Gessler et al., 1990; Glaser et al., 1989; Koufos et mental retardation; WT1, Wilms' tumor 1; WTAP, Wilms' tumor 1 asso- al., 1989; Reeve et al., 1989). Third, a locus for familial ciated protein Wilms' tumor, which accounts for only 1% of all Wilms' * Corresponding author. Tel.: 131-71-5276136; fax: 131-71-5276284. E-mail address: [email protected] ,A.G. Jochemsen). tumors, is not linked to chromosome 11 ,Grundy et al., 0378-1119/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S0378-1119,01)00593-5 142 V. Scharnhorst et al. / Gene 273 .2001) 141±161 1988), but instead maps to other chromosomal regions native splice donor site at the end of exon 9 results in ,Rahman et al., 1996, 1997; Slater and Mannens, 1992), incorporation of three additional amino acids, lysine, threo- demonstrating that Wilms' tumors are genetically heteroge- nine and serine ,KTS), between the third and fourth zinc neous and that at least three candidate genes are implicated ®ngers. The ratio of the different WT1 splice variants was in their development. found to be conserved between normal fetal kidney, Wilms' So far, the Wilms' tumor 1 gene ,WT1) at 11p13 is the tumors and several tissues of the murine genitourinary only gene involved in development of Wilms' tumor that system. The mRNA isoform containing both splice inserts has been cloned ,Call et al., 1990; Gessler et al., 1990) and is the most prevalent variant in both human and mouse, classi®ed as a tumor suppressor gene. It is now recognized whereas the least common is the transcript missing both that WT1 is homozygously mutated in 5±10% of Wilms' inserts ,Haber et al., 1991). These ®ndings were later tumors ,Gessler et al., 1994; Little and Wells, 1997; Little extended by a report describing that splicing of exon 5 is et al., 1992). differentially regulated in a species-, tissue- and develop- mental stage-speci®c manner, while the 1KTS/2KTS ratio is maintained in all cell types tested ,Renshaw et al., 1997). 2. The WT1 gene, mRNAs and proteins Additional WT1 mRNAs are generated through RNA edit- ing at nucleotide 839 of the WT1 mRNA that replaces The human WT1 gene spans about 50 kb at chromosome leucine 280 in WT1 proteins by proline ,Sharma et al., locus 11p13 ,Call et al., 1990; Gessler et al., 1990). It 1994), although the frequency of RNA editing might be comprises ten exons and encodes mRNAs of approximately signi®cantly lower than initially published ,Mrowka and 3 kb ,Call et al., 1990; Gessler et al., 1992). Schedl, 2000). The WT1 gene may thus produce eight differ- In mammals, exons 5 and 9 of WT1 are alternatively ent mRNA isoforms, suggesting that each isoform has a spliced, giving rise to four different splice isoforms ,Fig. distinct contribution to the function of the WT1 gene and 1) ,Gessler et al., 1992; Haber et al., 1991). In all other that balanced expression of the isoforms is essential for vertebrates tested, exon 5 is not present in the WT1 gene, proper WT1 function. so that only two different mRNA transcripts are generated Depending on the absence or presence of the two splice ,Kent et al., 1995). Inclusion of exon 5 inserts 17 amino inserts, the WT1 proteins have molecular masses of 52±54 acids between the proline and glutamine-rich amino-termi- kDa ,Morris et al., 1991). The WT1,2/2) protein with a nus and the zinc-®nger domain of WT1.