Suppression of prostate tumor cell growth in vivo by WT1, the Wilms' tumor suppressor gene

Fraizer, Gail; Leahy, Rachel; Priyadarshini, Subhadra; Graham, Kylie; Delacerda, Jorge; Diaz, Miguel

doi:10.3892/ijo.24.3.461

Cited by 22 publications

(23 citation statements)

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“…17 The ability of WT1 to induce growth suppression and suppress tumorigenicity in mice also highlights its role as a tumor suppressor. [18][19][20] For example, ectopic expression of WT1 in kidney-derived RM1 cells results in a reduced number of colonies in cell culture. 21 The stable introduction of the WT1 À/ þ isoform into G401, a kidney-derived tumor cell line that does not express endogenous WT1, alters cellular morphology and reduces tumor formation in athymic nude mice.…”

Section: Wt1 the Transcription Factormentioning

confidence: 99%

A tumor suppressor and oncogene: the WT1 story

et al. 2007

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The Wilms' tumor 1 (WT1) gene encodes a transcription factor important for normal cellular development and cell survival. The initial discovery of WT1 as the causative gene in an autosomal-recessive condition identified it as a tumor suppressor gene whose mutations are associated with urogenital disease and the development of kidney tumors. However, this view is not in keeping with the frequent finding of wild-type, full-length WT1 in human leukemia, breast cancer and several other cancers including the majority of Wilms' tumors. Rather, these observations suggest that in those conditions, WT1 has an oncogenic role in tumor formation. In this review, we explore the literature supporting both views of WT1 in human cancer and in particular human leukemias. To understand the mechanism by which WT1 can do this, we will also examine its functional activity as a transcription factor and the influence of protein partners on its dual behavior.

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Section: Wt1 the Transcription Factormentioning

confidence: 99%

A tumor suppressor and oncogene: the WT1 story

et al. 2007

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“…WT-1-induced apoptosis has been implicated in the actual development of the tumor (38,41). In prostate cancer, WT-1 suppressed tumor cell growth, regulated the androgen-signaling pathway, and inhibited vascular endothelial growth factor expression, all of which are essential for tumor growth inhibition (42,43). Although halofuginone induced a significant increase in WT-1 synthesis in both xenografts used, the respective chemotherapies induced WT-1 synthesis to a greater extent (Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect

Sheffer

Leon

Pinthus

et al. 2007

Molecular Cancer Therapeutics

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Stromal myofibroblasts play an important role in tumor progression. The transition of fibroblasts to myofibroblasts is characterized by expression of smooth muscle genes and profuse synthesis of extracellular matrix proteins. We evaluated the efficacy of targeting fibroblast-to-myofibroblast transition with halofuginone on tumor progression in prostate cancer and Wilms' tumor xenografts. In both xenografts, low doses of halofuginone treatment, independent of the route of administration, resulted in a trend toward inhibition in tumor development. Moreover, halofuginone synergizes with low dose of docetaxel in prostate cancer and vincristine and dactinomycin in Wilms' tumor xenografts, resulting in significant reduction in tumor volume and weight comparable to the effect observed by high doses of the respective chemotherapies.

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“…WT1 is also involved in the development of other organs including spleen, heart, and liver (10)(11)(12). In cell culture systems WT1 generally acts as a growth suppressor (13)(14)(15)(16)(17)(18) but its overexpression in a number of tumor types such as colon and thyroid (19,20) suggests that it may act as an oncogene as well. Accordingly knockdown of WT1 led to decreased growth of a Wilms tumor cell line suggesting a permissive role in growth in some cases of Wilms tumor (21).…”

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An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1

Kim

McGarry

Broin

et al. 2009

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

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WT1, a critical regulator of kidney development, is a tumor suppressor for nephroblastoma but in some contexts functions as an oncogene. A limited number of direct transcriptional targets of WT1 have been identified to explain its complex roles in tumorigenesis and organogenesis. In this study we performed genome-wide screening for direct WT1 targets, using a combination of ChIP-ChIP and expression arrays. Promoter regions bound by WT1 were highly G-rich and resembled the sites for a number of other widely expressed transcription factors such as SP1, MAZ, and ZNF219. Genes directly regulated by WT1 were implicated in MAPK signaling, axon guidance, and Wnt pathways. Among directly bound and regulated genes by WT1, nine were identified in the Wnt signaling pathway, suggesting that WT1 modulates a subset of Wnt components and responsive genes by direct binding. To prove the biological importance of the interplay between WT1 and Wnt signaling, we showed that WT1 blocked the ability of Wnt8 to induce a secondary body axis during Xenopus embryonic development. WT1 inhibited TCF-mediated transcription activated by Wnt ligand, wild type and mutant, stabilized ␤-catenin by preventing TCF4 loading onto a promoter. This was neither due to direct binding of WT1 to the TCF binding site nor to interaction between WT1 and TCF4, but by competition of WT1 and TCF4 for CBP. WT1 interference with Wnt signaling represents an important mode of its action relevant to the suppression of tumor growth and guidance of development.ChIP-ChIP ͉ microarray ͉ tumor suppressor T he genetic etiology of Wilms tumorigenesis is heterogeneous including loss-of-imprinting of IGF2 (1), deletions and mutations of WT1 (reviewed in ref.2) and the recently identified WTX (3) genes. In addition, somatic mutations in ␤-catenin leading to a stabilized protein are found in 15% of cases and curiously almost all of these mutation cases are found in patients lacking functional WT1 alleles (4-7).The WT1 tumor suppressor gene encodes a zinc finger transcription factor, possibly yielding up to 32 different isoforms (8). The major isoforms differ in the presence or absence of amino acids KTS in the zinc finger region and the presence or absence of a 17-aa stretch in the middle of the protein. The ϪKTS isoforms have been linked to DNA binding-mediated transcriptional control whereas the ϩKTS isoforms have been implicated in RNA processing as well (9). Renal agenesis in the Wt1 knockout mouse and the presence of constitutional mutations in WT1 in a number of renal developmental syndromes indicate a critical role for WT1 in kidney development.

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Suppression of prostate tumor cell growth in vivo by WT1, the Wilms' tumor suppressor gene

Cited by 22 publications

References 0 publications

A tumor suppressor and oncogene: the WT1 story

A tumor suppressor and oncogene: the WT1 story

Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect

An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1

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