A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N'-methylurea.

Sharma, Prem M.; Bowman, M.E.; Yu, Baofa; Sukumar, Saraswati

doi:10.1073/pnas.91.21.9931

Cited by 41 publications

(31 citation statements)

References 40 publications

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“…Therefore, we used in vitro phosphorylation of WT1 protein to map the PKA phosphorylation sites and to investigate the eects of phosphorylation. To test whether Ser-365 and Ser-393 were phosphorylated, we mutated Ser-365 and Ser-393 in His-WT1ZnF to Phe, which mimics the mutation observed at Ser-365 in a pre-B cell line (Call et al, 1990) and in a rat kidney tumor induced by N-nitroso-N'-methylurea (Sharma et al, 1994). Wild type and mutant His-WT1ZnF proteins phosphorylated by PKA were subjected to tryptic peptide mapping.…”

Section: Resultsmentioning

confidence: 99%

“…After incubation with BAP, the fusion protein was eluted from the beads with elution buer and then subjected to EMSA. Arrows indicate DNA/WT1 complex (WT1) or free probe DNA (F) c mock wt N'-methylurea (Sharma et al, 1994), we made and tested a Ser-365 to Phe WT1 mutant. The F365 mutant also showed signi®cant resistance to PKA-mediated inhibition of DNA-binding activity (Figure 8a).…”

Section: Resultsmentioning

confidence: 99%

“…The importance of PKA-mediated phosphorylation of WT1 is underscored by the ®nding that Ser-365 is mutated to Phe in two dierent types of transformed cell, namely in N-nitroso-N'-methylurea-induced rat embryonic kidney tumors, which resemble Wilms' tumor (Sharma et al, 1994), and in a human pre-B cell line (Call et al, 1990). Analysis of Phe-365 mutant WT1 shows that it has a dierent DNA-binding preference to that of wild type WT1 (Bickmore et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the DNA-binding and transcriptional repression activity of the Wilms' tumor gene product, WT1, by cAMP-dependent protein kinase-mediated phosphorylation of Ser-365 and Ser-393 in the zinc finger domain

et al. 1997

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The Wilms' tumor suppressor gene, WT1, encodes a transcription factor in the zinc ®nger family, which binds to GC-rich sequences and functions as a transcriptional activator or repressor. The WT1 protein plays a crucial role in urogenital development in mammals and its function is thought to be conserved during vertebrate evolution. Although accumulating evidence suggests that WT1 regulates a subset of genes including growth factor and growth factor receptor genes, little is known about regulators or signal cascades that could modulate the function of WT1. In this study, we show that the WT1 protein expressed exogenously in ®broblasts was phosphorylated in vivo, and that treatment with forskolin, which activates the cAMP-dependent protein kinase (PKA) in vivo, induced phosphorylation of additional sites in WT1. We identi®ed the forskolin-induced phosphorylation sites as Ser-365 and Ser-393, which lie in the zinc ®nger domain in zinc ®ngers 2 and 3, respectively. PKA phosphorylated WT1 at Ser-365 and Ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the DNA-binding activity of WT1 in vitro. Using WT1 mutants in which Ser-365 and Ser-393 were mutated to Ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of DNA binding in vivo. Thus, coexpression of the PKA catalytic subunit with wild type WT1 reduced the level of WT1 DNA-binding activity detected in nuclear extracts, and decreased transcriptional repression activity in vivo. In contrast to wild type WT1, all of the phosphorylation site mutants retained signi®cant DNAbinding activity and repression activity in the presence of PKA. Analysis of the mutants showed that phosphorylation of Ser-365 and Ser-395 had additive inhibitory eects on WT1 DNA-binding in vivo and that phosphorylation at both sites was required for neutralization of repression activity. Therefore, we conclude that PKA modulates the activity of WT1 in vivo through phosphorylation of Ser-365 and Ser-393, which inhibits DNA binding. This in turn results in a decrease in WT1 transcriptional repression. Our ®ndings provide the ®rst evidence that the function of WT1 can be modulated by its phosphorylation in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of the DNA-binding and transcriptional repression activity of the Wilms' tumor gene product, WT1, by cAMP-dependent protein kinase-mediated phosphorylation of Ser-365 and Ser-393 in the zinc finger domain

et al. 1997

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“…Homozygous PAX2 mutations have not been described in humans although known kindreds with kidney and Mullerian malformations superficially resemble the (female) mouse null-mutants (22,27). PAX2 and PAX8 are overexpressed in Wilms tumor (20,(28)(29)(30), a malignant neoplasm containing tissues resembling the embryonic kidney, and also in renal cell carcinoma (31). Thus, in mice and humans, a deficiency of metanephric PAX2 protein is associated with growth failure while overexpression of the same protein is associated with cyst or tumor formation.…”

Section: Introductionmentioning

confidence: 99%

The PAX2 tanscription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations.

Winyard

Risdon

Sams³

et al. 1996

J. Clin. Invest.

162

142

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Human dysplastic kidneys are developmental aberrations which are responsible for many of the very young children with chronic renal failure. They contain poorly differentiated metanephric cells in addition to metaplastic elements. We recently demonstrated that apoptosis was prominent in undifferentiated cells around dysplastic tubules (Winyard, P.J.D., J. Nauta, D.S. Lirenman, P. Hardman, V.R. Sams, R.A. Risdon, and A.S. Woolf. 1996. Kidney Int. 49:135-146), perhaps explaining the tendency of some of these organs to regress. In contrast, apoptosis was rare in dysplastic epithelia which are thought to be ureteric bud malformations. On occasion, these tubules form cysts which distend the abdominal cavity (the multicystic dysplastic kidney) and dysplastic kidneys may rarely become malignant. We now demonstrate that dysplastic tubules maintain a high rate of proliferation postnatally and that PAX2, a potentially oncogenic transcription factor, is expressed in these epithelia. In contrast, both cell proliferation and PAX2 are downregulated during normal maturation of human collecting ducts. We demonstrate that BCL2, a protein which prevents apoptosis in renal mesenchymal to epithelial conversion, is expressed ectopically in dysplastic kidney epithelia. We propose that dysplastic cyst formation may be understood in terms of aberrant temporal and spatial expression of master genes which are tightly regulated in the normal program of human nephrogenesis.

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“…55,75 Furthermore, rat models have been developed using strains of SpragueDawley and Noble Hooded rats, which have demonstrated nephroblastoma development as a spontaneous process 31,59 as well as through experimental induction using chemical carcinogenesis. 32,79 With the exception of lymphoma, nephroblastomas represent the most common primary renal neoplasm in fish, having been reported in both spontaneous and carcinogen-induced instances and affecting a wide variety of fish species. Epizootics of spontaneous nephroblastoma have been reported in over 60 Japanese eels, 56,64 while individual cases have been reported in European eels (Anguilla argentina), 21 striped bass (Morone saxatilis), 38 koi (Cyprinus carpio), 84 Crucian carp (Carassius carassius), 10 Japanese dace (Tribolodon hakonensis), 58 smelt, 42 Siamese fighting fish (Betta splendens), 52 sockeye salmon (RTLA), rose bitterling (Rhodeus ocellatus), 34 banded cichlid (Heros severus), 24 and rainbow trout.…”

Section: Nephroblastomasmentioning

confidence: 99%

Neoplasms of the Urinary Tract in Fish

2013

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The veterinary literature contains scattered reports of primary tumors of the urinary tract of fish, dating back to 1906. Many of the more recent reports have been described in association with the Registry of Tumors in Lower Animals, and most of the spontaneous neoplasms of the kidney and urinary bladder are single case reports. In rare instances, such as described in nephroblastomas of Japanese eels and tubular adenomas/adenocarcinomas of Oscars, there is suggestion of a genetic predisposition of certain populations to specific renal neoplasms, environmental carcinogenesis, or potentially an unknown infectious etiology acting as a promoter. Hematopoeitic neoplasms have been infrequently described as primary to the kidney of a variety of fish species, and therefore those case reports of renal lymphoma and plasmacytic leukemia are addressed within the context of this review.Keywords fish and marine animals, wildlife, urinary tract, oncologyBetween 30 000 and 40 000 species of fish have been reported in the literature and included in a variety of taxonomic classes falling under the infraphylum Gnathostomata or jawed vertebrates, which further consists of the extant class Chondrichthyes or cartilaginous fish and superclass Osteichthyes or the bony fish. 37 Within that enormous number of species, there is an extraordinary variety of structure and physiology, with species ranging in size from the smallest recorded fish (Paedocypris progenetica), measuring a mere 7.9 mm, 48 to the whale shark (Rhincodon typus), measuring up to 20 m in length. 15 It is therefore reasonable to expect that the pathology of fish encompasses an immense domain of entities and pathogeneses, representing a boundless field of potential discovery in veterinary pathology, particularly concerning spontaneous neoplastic disorders. The current paucity of information is due in large part to the environment in which the subjects live, the lack of our ability to track individuals throughout their range, and the fact that autolysis and predation affect the vast majority of samples, leaving the pathologist with a limited caseload of spontaneous neoplasms within wild populations. On the other hand, zoo and aquarium populations, private tropical and marine aquaria, and farmed fish are providing veterinary pathologists with a steady flow of novel entities and new interactions between host species and disease.The following review of neoplastic disease in the urinary system of bony and cartilaginous fishes relies heavily on the body of knowledge accumulated by the National Cancer Institute's Registry of Tumors in Lower Animals (RTLA) (Experimental Pathology Laboratories, Inc, Sterling, VA), which were donated from myriad sources as well as from the diligence of those researchers who have published their findings in the international literature. In addition, other sources were consulted as part of this review to include the Armed Forces Institute of Pathology (AFIP) archives, the Smithsonian National Zoo, department of pathology, and through the gene...

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A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N'-methylurea.

Cited by 41 publications

References 40 publications

Inhibition of the DNA-binding and transcriptional repression activity of the Wilms' tumor gene product, WT1, by cAMP-dependent protein kinase-mediated phosphorylation of Ser-365 and Ser-393 in the zinc finger domain

Inhibition of the DNA-binding and transcriptional repression activity of the Wilms' tumor gene product, WT1, by cAMP-dependent protein kinase-mediated phosphorylation of Ser-365 and Ser-393 in the zinc finger domain

The PAX2 tanscription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations.

Neoplasms of the Urinary Tract in Fish

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