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

Udtha, Malini; Lee, Sang Joon; Alam, Rita; Coombes, Kevin R.; Huff, Vicki

doi:10.1038/sj.onc.1206597

Cited by 37 publications

(23 citation statements)

References 31 publications

(30 reference statements)

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“…Transfection of WT1 into Wilms' tumor cells that lacked WT1 resulted in growth arrest, further supporting the role of WT1 as a tumor-suppressor gene. Most recently, Udtha et al (2003) have confirmed that c-myc expression is 2.33-fold higher in Wilms' tumors carrying WT1-inactivating mutations than in WT1 wildtype tumors using cDNA microarray, elucidating the tumor repression function of WT1 in Wilms' tumors. Consistent with this observation was the finding that WT1 can repress the expression of cancer-related proteins such as c-myc, hTERT and bcl-2, and enhance the expression of antiproliferative proteins such as p21 in cell lines (Hewitt et al, 1995;Englert et al, 1997;Oh et al, 1999).…”

Section: Discussionmentioning

confidence: 62%

Transcriptional activation of c-myc proto-oncogene by WT1 protein

et al. 2004

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The Wilms' tumor 1 gene (WT1) plays an essential role in urogenital development and malignancy. Through DNA binding, WT1 can either enhance or repress transcription depending on the context of the DNA-binding sites or the cell type in which it is expressed. WT1 is overexpressed in a variety of human cancers, including leukemia and breast cancer; in these diseases, the expression of WT1 is associated with a poor prognosis. To determine how WT1 affects c-myc expression in the context of breast cancer cells, we have examined the ability of both endogenous and exogenous WT1 proteins in breast cancer cells to bind to the c-myc promoter in vivo. Using c-myc-promoterdriven luciferase constructs, we found that different forms of WT1 could enhance the expression of the reporter. Unlike other studies where WT1 is reported to be a negative regulator of c-myc, we found that both the À and þ KTS forms of WT1 could act to enhance c-myc expression, depending on the cell type. The WT1-binding site near the second major transcription start site of the cmyc promoter was confirmed to be involved in upregulation of human c-myc by WT1. Finally, we demonstrated that overexpression of WT1 induced a significant increase in the abundance of endogenous c-myc protein in breast cancer cells, consistent with the upregulation of c-myc transcription following WT1 induction. These observations strongly argue that in the case of breast cancer WT1 is functioning as an oncogene in part by stimulating the expression of c-myc.

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Section: Discussionmentioning

confidence: 62%

Transcriptional activation of c-myc proto-oncogene by WT1 protein

et al. 2004

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“…The allele-discriminating probes were 5Ј TTT TCC CGG TCC 3Ј (wild type) and 5Ј TTT TCC TGG TCC GAC 3Ј (R394W mutant). Assays were performed as previously described (43).…”

Section: Methodsmentioning

confidence: 99%

The Wt1^+/R394W Mouse Displays Glomerulosclerosis and Early-Onset Renal Failure Characteristic of Human Denys-Drash Syndrome

Gao¹,

Maiti²,

Sun³

et al. 2004

Molecular and Cellular Biology

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Renal failure is a frequent and costly complication of many chronic diseases, including diabetes and hypertension. One common feature of renal failure is glomerulosclerosis, the pathobiology of which is unclear. To help elucidate this, we generated a mouse strain carrying the missense mutation Wt1 R394W, which predisposes humans to glomerulosclerosis and early-onset renal failure (Denys-Drash syndrome [DDS]). Kidney development was normal in Wt1؉/R394W heterozygotes. However, by 4 months of age 100% of male heterozygotes displayed proteinuria and glomerulosclerosis characteristic of DDS patients. This phenotype was observed in an MF1 background but not in a mixed B6/129 background, suggestive of the action of a strain-specific modifying gene(s). WT1 encodes a nuclear transcription factor, and the R394W mutation is known to impair this function. Therefore, to investigate the mechanism of Wt1 R394W-induced renal failure, the expression of genes whose deletion leads to glomerulosclerosis (NPHS1, NPHS2, and CD2AP) was quantitated. In mutant kidneys, NPHS1 and NPHS2 were only moderately downregulated (25 to 30%) at birth but not at 2 or 4 months. Expression of CD2AP was not changed at birth but was significantly upregulated at 2 and 4 months. Podocalyxin was downregulated by 20% in newborn kidneys but not in kidneys at later ages. Two other genes implicated in glomerulosclerosis, TGFB1 and IGF1, were upregulated at 2 months and at 2 and 4 months, respectively. It is not clear whether the significant alterations in gene expression are a cause or a consequence of the disease process. However, the data do suggest that Wt1 R394W-induced glomerulosclerosis may be independent of downregulation of the genes for NPHS1, NPHS2, CD2AP, and podocalyxin and may involve other genes yet to be implicated in renal failure. The Wt1 R394W mouse recapitulates the pathology and disease progression observed in patients carrying the same mutation, and the mutation is completely penetrant in male animals. Thus, it will be a powerful and biologically relevant model for investigating the pathobiology of the earliest events in glomerulosclerosis.Glomerulosclerosis, whether primary or secondary to other disease processes, is a key and common feature of progressive renal failure, which is a major cause of morbidity and mortality in the United States. Although several genetic and environmental insults are known to cause primary glomerulosclerosis, the cellular mechanism by which they initiate this process is still largely unknown. A knowledge of these mechanisms would greatly aid in identifying strategies to prevent or slow the development of glomerulosclerosis, regardless of its etiology.Glomeruli are complex and specialized structures responsible for blood filtration in the kidney and are targets of injury in a number of human diseases. The major functional features of the glomerulus are capillary loops lined with fenestrated endothelial cells, supporting mesangial cells, the glomerular basement membrane (GBM), and podocytes. The "octopuslike" ...

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“…In the last decade, the identification of genes in different types of human cancer has already been performed using this technology (14)(15)(16)(17)(18). In addition, HCC has already been analyzed by microarray techniques (19)(20)(21)(22).…”

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confidence: 99%

Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma

Hass

Vogel

Scheurlen

et al. 2016

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

Cited by 37 publications

References 31 publications

Transcriptional activation of c-myc proto-oncogene by WT1 protein

Transcriptional activation of c-myc proto-oncogene by WT1 protein

The Wt1^+/R394W Mouse Displays Glomerulosclerosis and Early-Onset Renal Failure Characteristic of Human Denys-Drash Syndrome

Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma

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

Cited by 37 publications

References 31 publications

Transcriptional activation of c-myc proto-oncogene by WT1 protein

Transcriptional activation of c-myc proto-oncogene by WT1 protein

The Wt1+/R394W Mouse Displays Glomerulosclerosis and Early-Onset Renal Failure Characteristic of Human Denys-Drash Syndrome

Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma

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The Wt1^+/R394W Mouse Displays Glomerulosclerosis and Early-Onset Renal Failure Characteristic of Human Denys-Drash Syndrome