Fine structure analysis of the WT1 gene in sporadic Wilms tumors.

Varanasi, Ramani; Bardeesy, Nabeel; Ghahremani, Majid; Petruzzi, Mary-Jane; Nowak, Norma J.; Adam, Mohammed; Grundy, Paul E.; Shows, Thomas B.; Pelletier, Jerry

doi:10.1073/pnas.91.9.3554

Cited by 122 publications

(68 citation statements)

References 25 publications

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“…One Wilms tumor gene (WT1) has been identified and mapped to 11p13 (Call et al, 1990;Gessler et al, 1990). The WT1 gene encoding a zinc-finger transcription factor is described to be mutated in 10-15% of sporadic Wilms tumors (Gessler et al, 1994;Varanasi et al, 1994). These same tumors often also harbour mutations in b-catenin (CTNNB1) (Maiti et al, 2000), implicating a role of Wnt pathway in the pathogenesis of Wilms tumor.…”

Section: Discussionmentioning

confidence: 99%

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

et al. 2006

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Inactivation of the HRPT2 gene encoding parafibromin was recently linked to the familial hyperparathyroidismjaw tumor syndrome. Patients with this syndrome carry an increased risk of parathyroid and renal tumors. To determine the relevance of HRPT2 for sporadic renal tumors, clear cell, papillary and chromophobe renal cell carcinomas as well as oncocytomas and Wilms tumors were analysed for HRPT2 gene alterations. Loss of heterozygosity (LOH) of HRPT2 was found in seven of 56 (12.5%) clear cell, three of 14 (21%) papillary, six of 10 (60%) chromophobe renal cell carcinomas, three of eight (38%) oncocytomas and four of 10 (40%) Wilms tumors. In addition, two novel HRPT2 point mutations, causing K34Q and R292K changes in parafibromin, were detected in one clear cell carcinoma and one Wilms tumor, respectively. These tumors displayed LOH of the remaining wild-type allele, but interestingly no von HippelLindau (VHL) mutation. Functional analysis revealed that the K34Q mutant species of parafibromin is, unlike wild-type protein, defective in suppressing cyclin D1 expression in vivo. Taken together, these results suggest that renal cancer-associated mutations in parafibromin occur in the absence of VHL mutation, which in turn may contribute to constitutively elevated cyclin D1 expression and abnormal cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

et al. 2006

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“…The majority of DDS individuals harbor wtl missense mutations within zinc fingers II and III which are thought to behave in a dominant-negative fashion [20,21]. Consistent with this idea is the recent demonstration that WT1 can oligomerize, that mutant WT1 protein can antagonize activity of wild-type protein [22,23], and that some WT1 missense mutations in WTs appear to be in a heterozygous configuration [2,4,11].…”

Section: Introductionmentioning

confidence: 85%

Identification of nuclear localization signals within the zinc fingers of the WT1 tumor suppressor gene product

et al. 1996

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WT1 encodes a zinc finger protein with a key role in urogenital development that is inactivated in a subset of Wilms' tumors. This tumor suppressor gene product contains an aminoterminal dimerization domain required for trans-inhibition of wild-type WT1 activity by mutants defective for DNA binding. In the course of characterizing truncation mutants of WT1, we noted that the WT1 zinc fingers contain two functionally independent targeting signals required for nuclear localization of the protein. These novel signals lie within zinc fingers I and within zinc f'mgers II and Ill. We demonstrate that nuclear targeting of the WT1 homodimerization domain functionally antagonizes activity of the wild-type protein activity.

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“…The only Wilmstumor gene identified to date, WT1 on chromosome 11p13 is vital for normal genitourinary development (Call et al, 1990;Gessler et al, 1990;Kreidberg et al, 1993). Mutations that inactivate WT1 function are observed in about 5-20% of Wilmstumors (Gessler et al, 1994;Varanasi et al, 1994;Huff, 1998).…”

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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Fine structure analysis of the WT1 gene in sporadic Wilms tumors.

Abstract: ABSTRACT

Cited by 122 publications

References 25 publications

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

Identification of nuclear localization signals within the zinc fingers of the WT1 tumor suppressor gene product

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

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