Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development

Bruening, Wendy; Bardeesy, Nabeel; Silverman, Bernard L.; Cohn, Richard A.; Machin, Geoffrey A.; Aronson, Andrew J.; Housman, David E.; Pelletier, Jerry

doi:10.1038/ng0592-144

Cited by 187 publications

(108 citation statements)

References 31 publications

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“…4). The discovery of a splicing lesion in individuals with DDS supports the dominant-negative model, since the primary sequence of the WT1 isoforms in these individuals are normal and unlikely to exhibit a gain of function [33]. Rather, it is likely that deregulation of the ratio of WT1 isoforms is responsible for the observed phenotype.…”

Section: Discussionmentioning

confidence: 85%

Identification of nuclear localization signals within the zinc fingers of the WT1 tumor suppressor gene product

et al. 1996

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WT1 encodes a zinc finger protein with a key role in urogenital development that is inactivated in a subset of Wilms' tumors. This tumor suppressor gene product contains an aminoterminal dimerization domain required for trans-inhibition of wild-type WT1 activity by mutants defective for DNA binding. In the course of characterizing truncation mutants of WT1, we noted that the WT1 zinc fingers contain two functionally independent targeting signals required for nuclear localization of the protein. These novel signals lie within zinc fingers I and within zinc f'mgers II and Ill. We demonstrate that nuclear targeting of the WT1 homodimerization domain functionally antagonizes activity of the wild-type protein activity.

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Section: Discussionmentioning

confidence: 85%

Identification of nuclear localization signals within the zinc fingers of the WT1 tumor suppressor gene product

et al. 1996

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“…Colonies were scored after 16 days after plating633 magni®cation of colonies in soft agar et al, 1995). The ratio of WT1(7KTS) to WT1(+KTS) isoforms is critical for normal WT1 function, since germline mutations within intron 9 which skew the ratio of spliced products towards the 7KTS isoforms, dramatically impairs urogenital system development and predisposes to WT (Bruening et al, 1992). From our results, it is clear that only the EWS/WT1(7KTS) is necessary for transformation ([at least in NIH3T3 cells]) and that EWS/WT1(+KTS) may not be necessary for DSCRT initiation or progression.…”

Section: Discussionmentioning

confidence: 99%

The desmoplastic small round cell tumor t(11;22) translocation produces EWS/WT1 isoforms with differing oncogenic properties

1998

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Structural alterations of the Wilms' tumor locus (WT1) at 11p13 have been implicated in the etiology of two human cancers ± Wilms' tumor (WT), a pediatric renal malignancy, and Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer of the abdomenal serosal lining with predilection for male adolescents. Germline mutations within the WT1 tumor suppressor gene predispose to WT and are associated with congenital malformations of the urogenital system, and somatic mutations are associated with initiation of transformation in WTs. In DSRCT, a recurrent translocation, t(11;22)(p13;q12), fuses the amino terminal domain of the EWS1 gene product to three of the four WT1 zinc ®ngers. Two EWS/WT1 isoforms are generated as a result of an alternative splicing event between zinc ®ngers III and IV, inserting or removing three amino acids (+KTS). We demonstrate that introduction of EWS/ WT1(7KTS) into NIH3T3 cells causes their tumorigenic transformation as determined by: formation of transformed foci on a monolayer of cells; anchorageindependent growth; and tumor formation in nude mice. EWS/WT1(+KTS) showed no transforming potential in these assays. These results indicate the oncogenic e ect of the t(11;22) translocation is mediated by the EWS/ WT1(7KTS) isoform and that fusion of the EWS amino terminal domain to the WT1 DNA binding domain produces a chimeric product showing a gain of function.

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“…Experiments using expression vectors to overexpress one WT1 isoform in the context of the endogenous four WT1 isoforms need to be interpreted with caution because the activity of the latter is likely to be perturbed. Clearly the ratio of WT1 isoforms is important for normal embryogenesis, given that mutations that affect splice-site selection at the second alternatively spliced exon (exon 9) deregulate WT1 gene expression and are associated with DDS (24 …”

Section: Discussionmentioning

confidence: 99%

Antagonism of WT1 activity by protein self-association.

Moffett

Bruening

Nakagama

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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Germline loss-of-function mutations at the Wilms tumor (WT) suppressor locus WTI are associated with a predisposition to WTs and mild genital system anomalies. In contrast, germ-line missense mutations within the WTI gene encoding the DNA-binding domain often yield a more severe phenotype consisting of WT, sexual ambiguity, and renal nephropathy. In this report, we demonstrate that the products of mutant alleles that impair DNA recognition can antagonize WT1-mediated transcriptional repression. We demonstrate that WT1 can self-associate in vitro and in vivo and that the responsible domain maps to the amino-terminal region of the protein. Oligomers of full-length protein form less efficiently or produce less stable complexes than oligomers between truncated polypeptides and full-length protein. Our data suggest a molecular mechanism to explain how WTI mutations may act in deregulating cellular proliferation and differentiation.

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Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development

Cited by 187 publications

References 31 publications

Identification of nuclear localization signals within the zinc fingers of the WT1 tumor suppressor gene product

Identification of nuclear localization signals within the zinc fingers of the WT1 tumor suppressor gene product

The desmoplastic small round cell tumor t(11;22) translocation produces EWS/WT1 isoforms with differing oncogenic properties

Antagonism of WT1 activity by protein self-association.

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