Increased expression of the insulin-like growth factor I receptor gene, IGF1R, in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product.

Werner, Haim; Re, Gian G.; Drummond, I A; Sukhatme, V P; Rauscher, F. J.; Sens, Donald A.; Garvin, A. Julian; LeRoith, Derek; Roberts, Charles T.

doi:10.1073/pnas.90.12.5828

Cited by 250 publications

(143 citation statements)

References 26 publications

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“…Many potential target genes that contain EGR1/WT1 binding sites in their promoters have been identified. They include the genes c-MYC, c-MYB, IGF1R, TGFB1, EGR1, RAR-a-1, TMP21, E-cadherin, N-myc, and CTGF (Madden et al, 1991;Werner et al, 1993;Dey et al, 1994;Goodyer et al, 1995;Hewitt et al, 1995;McCann et al, 1995;Englert et al, 1997;Zhang et al, 1999;Hosono et al, 2000;Stanhope-Baker and Williams, 2000). A second potential DNA-binding motif for WT1 consists of TCC repeats, which have been identified in the promoters of PDGFA (Wang et al, 1992) and EGFR (Englert et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors

et al. 2003

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Section: Introductionmentioning

confidence: 99%

Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors

et al. 2003

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“…Unlike the WT1 tumor suppressor gene, which generally acts as a transcriptional repressor, EWS/ WT1 is a potent transcriptional activator (Karnieli et al, 1996;Rauscher et al, 1994). EWS/WT1 recognizes the same DNA binding sites as WT1 and has been shown to activate transcription of the insulin-like growth factor-1 receptor gene (Karnieli et al, 1996;Rauscher et al, 1994), a gene whose expression can be repressed by WT1 (Werner et al, 1994(Werner et al, , 1995. Although the transforming potential of EWS/WT1 has never been demonstrated, deregulation of WT1 downstream targets by EWS/WT1 is thought to play a role in tumorigenesis of DSRCT.…”

Section: Introductionmentioning

confidence: 99%

The desmoplastic small round cell tumor t(11;22) translocation produces EWS/WT1 isoforms with differing oncogenic properties

1998

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Structural alterations of the Wilms' tumor locus (WT1) at 11p13 have been implicated in the etiology of two human cancers ± Wilms' tumor (WT), a pediatric renal malignancy, and Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer of the abdomenal serosal lining with predilection for male adolescents. Germline mutations within the WT1 tumor suppressor gene predispose to WT and are associated with congenital malformations of the urogenital system, and somatic mutations are associated with initiation of transformation in WTs. In DSRCT, a recurrent translocation, t(11;22)(p13;q12), fuses the amino terminal domain of the EWS1 gene product to three of the four WT1 zinc ®ngers. Two EWS/WT1 isoforms are generated as a result of an alternative splicing event between zinc ®ngers III and IV, inserting or removing three amino acids (+KTS). We demonstrate that introduction of EWS/ WT1(7KTS) into NIH3T3 cells causes their tumorigenic transformation as determined by: formation of transformed foci on a monolayer of cells; anchorageindependent growth; and tumor formation in nude mice. EWS/WT1(+KTS) showed no transforming potential in these assays. These results indicate the oncogenic e ect of the t(11;22) translocation is mediated by the EWS/ WT1(7KTS) isoform and that fusion of the EWS amino terminal domain to the WT1 DNA binding domain produces a chimeric product showing a gain of function.

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“…Reported target genes for the WT1 protein include both genes involved in growth regulation and genes necessary for induction of di erentiation, such as c-myc, bcl-2 (Hewitt et al, 1995), colony-stimulating factor-1 (CSF-1) (Harrington et al, 1993), transforming growth factor-b1 (TGF-b1) (Dey et al, 1994), insulin-like growth factor 1 receptor (IGF1R) (Werner et al, 1993), insulin-like growth factor II (IGF II) (Drummond et al, 1992), platelet-derived growth factor A-chain (PDGF-A) (Gashler et al, 1992) and retinoic acid receptor-a (RAR-a) (Goodyer et al, 1995). The WT1 protein has been shown to mediate either transcriptional repression or activation, depending on the architecture of the promoter under study and the cell lines in which the transfection assay were performed (Madden et al, , 1993Drummond et al, 1992;Maheswaran et al, 1993;Werner et al, 1993;Wang et al, 1993b).…”

Section: Introductionmentioning

confidence: 99%

Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program

et al. 1998

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The Wilms tumor gene, WT1, encodes a zinc-®nger DNA binding protein which is thought to function as a tissue speci®c transcription factor, regulating cell growth and di erentiation. High expression of WT1 has been detected in a range of acute leukemias. To elucidate a role for WT1 in leukemogenesis, we transfected the monoblastic cell line U937, which lacks detectable levels of endogenous WT1, with two isoforms of WT1. We showed that, in contrast to U937 control cells, cells constitutively expressing either of the isoforms, WT1(7KTS) or WT1(+KTS), did not respond to di erentiation induction by retinoic acid or vitamin D3, as judged by the capacity to reduce nitro blue tetrazolium and morphology. Although U937 cells expressing WT1 were hampered in their ability to di erentiate on incubation with retinoic acid and vitamin D3, the induced G1/G0-accumulation was similar to di erentiating control cells treated with inducers. Furthermore, distinct e ects on the maturation process were indicated by downregulation of the myeloid cell surface makers CD13 and CD15, while the upregulation of CD14 and CD11c on WT1 transfected cells was similar to control cells upon incubation with retinoic acid and vitamin D3. Taken together our results demonstrate that a constitutive expression of WT1 in the leukemic cell line U937 leads to impairment of di erentiation responses, indicating that a high expression of WT1 can contribute to the di erentiation block of acute leukemia.

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Increased expression of the insulin-like growth factor I receptor gene, IGF1R, in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product.

Abstract: Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema.

Cited by 250 publications

References 26 publications

Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors

Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors

The desmoplastic small round cell tumor t(11;22) translocation produces EWS/WT1 isoforms with differing oncogenic properties

Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program

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