A Pathologic Link between Wilms Tumor Suppressor Gene, WT1, and IFI16

Kim, Marianne K-H.; Mason, Jacqueline M.; Berkofsky-Fessler, Windy; Jiang, Lei; Choubey, Divaker; Grundy, Paul E.; Tycko, Benjamin; Licht, Jonathan D.

doi:10.1593/neo.07869

Cited by 22 publications

(26 citation statements)

References 24 publications

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“…For reasons that remain unclear, Wilms tumors appear very resistant to establishment as long-term cultures, and several early models such as SK-NEP-1 and G401 have later been proven to be tumors other than Wilms (10,11). In the present study, we have used a small panel of more recently described Wilms tumor cell lines derived from primary in vitro culture [17.94 (12), WT-CLS1 (13), CCG 99-11 (14), STA2A (15) We addressed the lack of in vitro preclinical data by studying the effect of targeting the IGF1R in these models by genetic and pharmacological means. We demonstrated that the small-molecule inhibitor NVP-AEW541 had a potent cytotoxic effect against Wilms tumor cells in vitro through down-regulation of PI3K and MAPK pathways, as well as cell cycle control genes such as CCNA2 and CCNB1, leading to a marked G 1 arrest and subsequent induction of apoptosis in a caspase-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition

Bielen¹,

Box

Perryman³

et al. 2012

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

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We have previously demonstrated an increased DNA copy number and expression of IGF1R to be associated with poor outcome in Wilms tumors. We have now tested whether inhibiting this receptor may be a useful therapeutic strategy by using a panel of Wilms tumor cell lines. Both genetic and pharmacological targeting resulted in inhibition of downstream signaling through PI3 and MAP kinases, G 1 cell cycle arrest, and cell death, with drug efficacy dependent on the levels of phosphorylated IGF1R. These effects were further associated with specific gene expression signatures reflecting pathway inhibition, and conferred synergistic chemosensitisation to doxorubicin and topotecan. In the in vivo setting, s.c. xenografts of WiT49 cells resembled malignant rhabdoid tumors rather than Wilms tumors. Treatment with an IGF1R inhibitor (NVP-AEW541) showed no discernable antitumor activity and no downstream pathway inactivation. By contrast, Wilms tumor cells established orthotopically within the kidney were histologically accurate and exhibited significantly elevated insulin-like growth factor–mediated signaling, and growth was significantly reduced on treatment with NVP-AEW541 in parallel with signaling pathway ablation. As a result of the paracrine effects of enhanced IGF2 expression in Wilms tumor, this disease may be acutely dependent on signaling through the IGF1 receptor, and thus treatment strategies aimed at its inhibition may be useful in the clinic. Such efficacy may be missed if only standard ectopic models are considered as a result of an imperfect recapitulation of the specific tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition

Bielen¹,

Box

Perryman³

et al. 2012

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

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“…To determine whether the activation of p53 in cells increases levels of the IFI16 protein through transcriptional mechanisms, we transfected Saos Pro72 or Saos Arg72 cells with IFI16-luc-reporter plasmid in which transcription of the luciferase reporter gene is driven by the 5 ¶-regulatory region (1.68 kb) of the IFI16 gene (31). As shown in Fig.…”

Section: Functional P53 Activates Transcription Of the Ifi16 Genementioning

confidence: 99%

Expression of an IFN-Inducible Cellular Senescence Gene, IFI16, Is Up-Regulated by p53

Song

Alimirah

Panchanathan

et al. 2008

Molecular Cancer Research

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IFN-inducible IFI16 protein (encoded by IFI16 gene at 1q23.1) is the human member of the IFN-inducible structurally related p200 family proteins. Increased expression of the IFI16 protein, a positive modulator of p53-mediated transcription, in normal old human diploid fibroblasts (HDF) is associated with cellular senescence-mediated cell growth arrest. However, the underlying mechanisms that contribute to transcriptional activation of the IFI16 gene in old HDFs remain to be elucidated. Here, we reported that functional activation of p53 in normal young HDFs and p53-null Saos2 cell line resulted in transcriptional activation of the IFI16 gene. We identified a potential p53 DNA-binding site (indicated as IFI16-p53-BS) in the 5 ¶-regulatory region of the IFI16 gene. Importantly, p53 bound to IFI16-p53-BS in a sequence-specific manner in gel-mobility shift assays. Furthermore, p53 associated with the 5 ¶-regulatory region of the IFI16 gene in chromatin immunoprecipitation assays. Interestingly, p53 associated with the regulatory region of the IFI16 gene only on treatment of cells with DNA-damaging agents or in the old, but not in the young, HDFs. Importantly, our promoter-reporter assays, which were coupled with site-directed mutagenesis of IFI16-p53-BS, showed that p53 activates transcription of the IFI16 gene in HDFs through the p53 DNA-binding site. Together, our observations provide support for the idea that up-regulation of IFI16 expression by p53 and functional interactions between IFI16 protein and p53 contribute to cellular senescence.

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“…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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confidence: 97%

“…WT1 target genes include CDKN1A (22), a negative regulator of the cell cycle; AREG (23), a facilitator of kidney differentiation; WNT4 (24), a stimulator of renal development; and SPRY1 (25), a critical intracellular regulator of receptor tyrosine kinase signaling and kidney development. Examination of gene expression in WT1 null and WT1 replete Wilms tumor specimens identified a gene (IFI16) not normally regulated or even expressed in the same subcellular compartment as WT1 but regulated in a pathological manner in tumors (21).…”

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confidence: 99%

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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A Pathologic Link between Wilms Tumor Suppressor Gene, WT1, and IFI16

Cited by 22 publications

References 24 publications

Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition

Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition

Expression of an IFN-Inducible Cellular Senescence Gene, IFI16, Is Up-Regulated by p53

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

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