RNA editing in the Wilms' tumor susceptibility gene, WT1.

Sharma, Prem M.; Bowman, M.E.; Madden, Stephen L.; Rauscher, Frank J.; Sukumar, Saraswati

doi:10.1101/gad.8.6.720

Cited by 167 publications

(92 citation statements)

References 46 publications

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“…The three WT1 carboxy-terminal zinc fingers show 64% identity to the three zinc fingers of the early growth response gene-1 (EGR-1) [7,8]. The mRNA contains two alternative sites of translation initiation [10], two alternatively spliced exons [11,12], and undergoes RNA editing [13], thus potentially encoding 16 different protein isoforms with predicted molecular masses of 52-65 kDa. The function of the alternative translation initiation event, or of the first alternatively spliced exon (exon V), has not been well defined, although exon V can repress transcription when fused to a heterologous DNA binding domain [14].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 1996

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“…Whether the editing of NF1 is mediated by APOBEC-1 together with novel trans-acting factors remains to be conclusively established (Skuse et al, 1996;Cappione et al, 1997). The third line of evidence that mRNA editing may be involved in oncogenesis is derived from an investigation of the Wilms tumor susceptibility gene WT1 (Sharma et al, 1994). The mRNA of WT1 can be edited from U to C at nucleotide position 839, changing codon 280 from CTC for leucine into CCC for proline (Sharma et al, 1994).…”

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confidence: 99%

“…The mRNA of WT1 can be edited from U to C at nucleotide position 839, changing codon 280 from CTC for leucine into CCC for proline (Sharma et al, 1994). The editing of WT1 mRNA is tissuespeci®c, temporally controlled and functionally important as the edited form of WT1 protein is less e cient in transcriptional repression than the unedited form (Sharma et al, 1994).…”

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confidence: 99%

Absence of APOBEC-1 mediated mRNA editing in human carcinomas

et al. 1999

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The transgene expression of the catalytic subunit APOBEC-1 of the apo B mRNA editing enzymecomplex can cause hepatocellular carcinoma in mice and rabbits. It has been proposed that aberrant editing of mRNA may represent a novel oncogenic principle. This investigation aimed to de®ne whether such aberrant hyperediting mediated by APOBEC-1 occurs in human carcinomas. Editing and hyperediting of apo B, NAT1 or NF1 mRNA was not identi®ed in any of 28 resected tumor specimens, including hepatocellular, bile duct, gastric, colorectal, pancreatic adeno-and neuroendocrine, lung adeno-, medullary thyroid and breast carcinoma, soft tissue sarcoma and neuroblastoma. In most types of carcinoma, signi®cant levels for full-length APOBEC-1 mRNA could not be detected. Low level expression of APOBEC-1 was found in colorectal and gastric carcinoma where most of the APOBEC-1 mRNA is inactivated by alternate splicing. The`auxiliary' components of the apo B mRNA editing enzyme-complex are missing in many tumors including colorectal and gastric carcinoma, but are highly expressed in hepatocellular, lung adeno-and breast carcinoma all of which lack APOBEC-1. Taken together, either APOBEC-1 or the`auxiliary' components of the apo B mRNA editing enzyme-complex or both are missing in human carcinomas resulting in the absence of mRNA editing. Currently, there is no evidence that aberrant editing mediated by APOBEC-1 contributes to the tumorigenesis of natural human carcinomas.

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“…The WT1 gene encodes multiple nuclear proteins by virtue of three di erent transcription start sites, RNA editing of a single nucleotide and two alternatively spliced regions; exon 5 (17 amino acids) and an alternate splice donor site after exon 9 Sharma et al, 1994;Bruening and Pelletier, 1996;Scharnhorst et al, 1999). The latter results in the addition of three amino acids (KTS) between exons 9 and 10.…”

Section: Introductionmentioning

confidence: 99%

Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1

Sim

Smith

et al. 2002

Oncogene

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The Wilms' tumour suppressor gene, WT1, encodes multiple nuclear protein isoforms, all containing four C-terminal zinc ®nger motifs. WT1 proteins can both activate and repress putative target genes in vitro, although the in vivo relevance of these putative target genes is often unveri®ed. WT1 mutations can result in Wilms' tumour and the Denys-Drash Syndrome (DDS) of infantile nephropathy, XY pseudohermaphroditism and predisposition to Wilms' tumour. We have established stable transfectants of the mouse mesonephric cell line, M15, which express WT1 harbouring a common DDS point mutation (R394W). A comparison of the expression pro®les of M15 and transfectant C2A was performed using Nylon-based arrays. Very few genes showed di erential expression. However Wnt-4, a member of the Wnt gene family of secreted glycoproteins, was downregulated in C2A and other similar clones. Doxycycline induction of WT1-A or WT1-D expression in HEK293 stable transfectants also elicited an elevation in Wnt4 expression. Wnt4 is critical for the mesenchyme-to-epithelial transition during kidney development, making it an attractive putative WT1 target. We have mapped human Wnt-4 gene to chromosome 1p35-36, a region of frequent LOH in WT, have characterized the genomic structure of the human Wnt-4 gene and isolated 9 kb of immediate promoter. While several potential WT1 binding sites exist within this promoter, reporter analysis does not strongly support the direct regulation of Wnt4 by WT1. We propose that Wnt-4 regulation by WT1 occurs at a more distant promoter or enhancer site, or is indirect.

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RNA editing in the Wilms' tumor susceptibility gene, WT1.

Cited by 167 publications

References 46 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

Absence of APOBEC-1 mediated mRNA editing in human carcinomas

Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1

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