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

Davies, Rachel; Calvio, Cinzia; Bratt, Eva; Larsson, Stefan; Lamond, Angus I.; Hastie, Nicholas D.

doi:10.1101/gad.12.20.3217

Cited by 216 publications

(179 citation statements)

References 39 publications

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“…Alternatively, WT1 ( þ Ex5/ þ KTS) could affect which E-cadherin splice forms are expressed. This isoform of WT1 has been implicated in regulation of alternative splicing (Davies et al, 1998), and perhaps this activity is responsible for the observed effect on E-cadherin localization. This would be consistent with a lack of effect of WT1 (ÀEx5/ÀKTS), which has not been implicated in the regulation of mRNA splicing.…”

Section: Discussionmentioning

confidence: 99%

“…The other alternative splice involves the use of one of the two distinct splice acceptor sites at the N-terminus of exon 10, resulting in the inclusion of three additional amino acids (KTS) in the larger protein isoform, altering the spacing of the zinc-fingers that compose the DNA-binding domain. The presence or absence of this so-called KTS insert has profound functional consequences for the mature protein, affecting both DNA-binding and subcellular localization, but the functional importance of exon 5 remains unclear (Larsson et al, 1995;Davies et al, 1998;Natoli et al, 2002;Reynolds et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Isoforms of Wilms’ tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells

et al. 2006

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The role of WT1 (Wilm's tumor suppressor gene) in breast cancer is controversial, with evidence for both tumorpromoting and tumor-suppressing activities. In order to address this question, we expressed different WT1 isoforms in the mammary epithelial cell line H16N-2, which does not express endogenous WT1. Cells were stably transfected with either WT1 (ÀEx5/ÀKTS) or WT1 ( þ Ex5/ þ KTS) under the control of the inducible metallothionein promoter. Induction of WT1 (ÀEx5/ ÀKTS) upregulated p21, causing a slowing of proliferation and a G2-phase cell cycle arrest. In artificial basement membrane, the WT1 (ÀEx5/ÀKTS) isoform promoted the appearance of highly organized acinar cellular aggregates. In contrast, WT1 ( þ Ex5/ þ KTS) had no effect on p21 or proliferation, but rather caused an epithelial-mesenchymal transition and a redistribution of E-cadherin from the cell membrane to the cytoplasm. This isoform also causes the cellular aggregates growing in artificial basement membrane to appear significantly less organized than control cells. Thus, different WT1 isoforms have distinct effects in this cell line, suggesting that depending on the ratio of WT1 isoform expression in mammary epithelial cells, WT1 could function to either promote or suppress a transformed phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Isoforms of Wilms’ tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells

et al. 2006

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“…3,[10][11][12] At least 36 isoforms of WT1 protein are produced from the same DNA template as a result of alternative transcription initiation, alternative pre-mRNA splicing, mRNA editing and alternative translation initiation. 1,3,5,10,[13][14][15][16][17][18] The four major WT1 isoforms are generated by an alternative splicing and vary in the presence or absence of so called 17AA insert (17 amino acids encoded by the whole exon 5) and KTS insert (according to the three amino acids leucinethreonine-serine encoded by the terminal sequence of exon 9)- [19][20][21][22][23] An alternative WT1 transcript, AWT1 (also short transcript, sWT1), maintains WT1 exonic structure between exons 2 and 10 but uses another first exon located in intron 1 of WT1 (exon 1a). It may otherwise exist in all splicing variants characteristic of WT1.…”

Section: Introductionmentioning

confidence: 99%

Real-time PCR quantification of major Wilms’ tumor gene 1 (WT1) isoforms in acute myeloid leukemia, their characteristic expression patterns and possible functional consequences

et al. 2012

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Wilms' tumor gene 1 (WT1) functions including some contradictory effects may be explained by the presence and interactions of its isoforms, however, their evaluation has been so far complicated by several technical problems. We designed unique quantitative PCR systems for direct quantification of the majorand verified their sensitivity, specificity and reproducibility in extensive testing. With this method we evaluated WT1 total and isoform expression in 23 normal bone marrow (BM) samples, 73 childhood acute myeloid leukemia (AML), 20 childhood myelodysplastic syndrome (MDS), 9 childhood severe aplastic anemia (SAA), 30 adult AML and 29 adult MDS patients. WT1 isoform patterns showed differences among these samples and clustered them into groups representing the specific diagnoses (Po0.0001). Isoform profiles were independent of total WT1 expression and possess certain common features-overexpression of isoform D and

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“…However, recent reports have shown evidence that WT1 is involved not only in transcriptional regulation in the nucleus but also in RNA metabolism and translational regulation in the cytoplasm. The binding of WT1 to splicing factors 25 and murine IGF-II mRNA 26 in vitro was demonstrated. Furthermore, nucleocytoplasmic shuttling of WT1 and the association of WT1 with actively translating polysomes were reported.…”

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confidence: 99%

Immunohistochemical detection of WT1 protein in a variety of cancer cells

et al. 2006

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WT1 was first identified as a tumor suppressor involved in the development of Wilms' tumor. Recently, oncogenic properties of WT1 have been demonstrated in various hematological malignancies and solid tumors. Because WT1 has been identified as a molecular target for cancer immunotherapy, immunohistochemical detection of WT1 in tumor cells has become an essential part of routine practice. In the present study, the expression of WT1 was examined in 494 cases of human cancers, including tumors of the gastrointestinal and pancreatobiliary system, urinary tract, male and female genital organs, breast, lung, brain, skin, soft tissues and bone by immunohistochemistry using polyclonal (C-19) and monoclonal (6F-H2) antibodies against WT1 protein. Staining for C-19 and 6F-H2 was found in 35-100 and 5-88% of the cases of each kind of tumor, respectively. WT1-positive tumors included tumor of the stomach, prostate, and biliary and urinary systems, and malignant melanomas. A majority of the positive cases showed diffuse or granular staining in the cytoplasm, whereas ovarian tumors and desmoplastic small round cell tumors frequently showed nuclear staining. Glioblastomas, some of soft tissue sarcomas, osteosarcomas, and malignant melanomas of the skin showed extremely strong cytoplasmic staining as compared with other tumors. Western blot analysis showed that WT1 protein was predominantly expressed in the cytoplasm of the tumor cells in two cases of lung adenocarcinoma, supporting the intracytoplasmic staining for WT1 using immunohistochemistry. Immunohistochemical detection with routinely processed histologic sections could provide meaningful information on the expression of WT1 in cancer cells.

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

Cited by 216 publications

References 39 publications

Isoforms of Wilms’ tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells

Isoforms of Wilms’ tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells

Real-time PCR quantification of major Wilms’ tumor gene 1 (WT1) isoforms in acute myeloid leukemia, their characteristic expression patterns and possible functional consequences

Immunohistochemical detection of WT1 protein in a variety of cancer cells

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