Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via multiple pathways

Sitaram, Raviprakash T.; Degerman, Sofie; Ljungberg, Börje; Andersson, Emma; Oji, Yusuke; Sugiyama, Haruo; Roos, Göran; Li, Aihong

doi:10.1038/sj.bjc.6605878

Cited by 34 publications

(38 citation statements)

References 43 publications

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“…Upon closer inspection of the target genes that we identified to be common to both isoforms, we found that they include several previously known WT1 targets, including BCL2-Like 1 (BCL2L1/BCLXL), 24 DNA (Cytosine-5)-Methyltransferase 3 Alpha (DNMT3A), 25 Platelet-Derived Growth Factor Alpha Polypeptide (PDGFA), 26 SMAD Family Member 3 (SMAD3), 27 and Vitamin D Receptor (VDR). 28 In conclusion, among our identified target genes that include previously known targets, WT1 -KTS and WT1 +KTS isoforms bind, to a large extent, to the same target genes, but in distinct locations, suggesting at least partially different molecular mechanisms.…”

Section: Wt1 -Kts and Wt1 +Kts Bind Different Locations Within The Samentioning

confidence: 99%

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

et al. 2016

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T he zinc finger transcription factor Wilms tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (±KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of the WT1 -KTS isoform at the expense of the WT1 +KTS isoform is associated with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with the involvement of WT1 in acute myeloid leukemia.

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Section: Wt1 -Kts and Wt1 +Kts Bind Different Locations Within The Samentioning

confidence: 99%

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

et al. 2016

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“…Initially, WT1 was described as a tumor suppressor gene in Wilms' tumor [15]. In clear cell renal carcinoma (ccRCC), we have demonstrated that WT1 can act as a tumor suppressor via multiple pathways leading to downregulation of hTERT [16]. Moreover, WT1 was found to bind directly the promoters of the downstream targets hTERT, cMyc and SMAD3 promoters [16].…”

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confidence: 99%

WT1 Enhances Proliferation and Impedes Apoptosis in KRAS Mutant NSCLC via Targeting cMyc

Wang

et al. 2015

Cell Physiol Biochem

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Background: A novel link between oncogenic KRAS signalling and WT1 was recently identified. We sought to investigate the role of WT1 and KRAS in proliferation and apoptosis. Methods: KRAS mutations and WT1 (cMyc) expression were detected using Sanger sequencing and real-time PCR in 77 patients with non-small cell lung cancer (NSCLC). Overexpression and knockdown of WT1 were generated with plasmid and siRNA via transient transfection technology in H1299 and H1568 cells. MTT assay for detection of cell proliferation, and TUNEL assay and proteomic profiler assay for apoptosis evaluation were carried out. Dual luciferase reporter assay and ChIP-PCR were performed to validate the effect of WT1 on the cMyc promoter. Results: KRAS mutations showed a negative impact on overall survival (OS). High expressions of WT1 and cMyc were associated with poor OS in KRAS mutant subgroup. The potential mechanisms that WT1 promotes proliferation and impedes apoptosis through affecting multiple apoptosis-related regulators in KRAS mutant NSCLC cells were identified. WT1 could activate cMyc promoter directly in KRAS mutant cells. Conclusion: The results suggest that WT1 and c-MYC expression is important for survival in KRAS mutant tumors as opposed to KRAS wild-type tumors. For treatment of KRAS mutant NSCLC, targeting WT1 and cMyc may provide alternative therapeutic strategies.

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“…10 WT1 was initially thought to be a tumor suppressor gene, but subsequent research uncovered its oncogenic role when it was demonstrated that WT1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma. 31 Menssen et al were the first group to show the expression of WT1 in human GBM. They reported a high WT1 expression in 63% of GBM cell lines.…”

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confidence: 99%

Wilms tumor 1 gene, CD97, and the emerging biogenetic profile of glioblastoma

Somasundaram

Ardanowski

Opalak

et al. 2014

FOC

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Glioblastoma multiforme (GBM) is the most common type of primary brain tumor, and current treatment regimens are only marginally effective. One of the most vexing and malignant aspects of GBM is its pervasive infiltration into surrounding brain tissue. This review describes the role of the Wilms tumor 1 gene (WT1) and its relationship to GBM. WT1 has several alternative splicing products, one of which, the KTS+ variant, has been demonstrated to be involved in the transcriptional activation of a variety of oncogenes as well as the inhibition of tumor suppressor genes. Further, this paper will examine the relationship of WT1 with CD97, a gene that codes for an epidermal growth factor receptor family member, an adhesion G-protein–coupled receptor, thought to promote tumor invasiveness and migration. The authors suggest that further research into WT1 and CD97 will allow clinicians to begin to deal more effectively with the infiltrative behavior displayed by GBM and design new therapies that target this deadly disease.

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Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via multiple pathways

Cited by 34 publications

References 43 publications

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

WT1 Enhances Proliferation and Impedes Apoptosis in KRAS Mutant NSCLC via Targeting cMyc

Wilms tumor 1 gene, CD97, and the emerging biogenetic profile of glioblastoma

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