Ornithine Decarboxylase Is a Transcriptional Target of Tumor Suppressor WT1

Li, Run Sheng; Law, G. Lynn; Seifert, Ronald A.; Romaniuk, Paul J.; Morris, David R.

doi:10.1006/excr.1998.4361

Cited by 25 publications

(15 citation statements)

References 49 publications

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“…The ornithine decarboxylase (ODC) gene was weakly expressed (ODC was only detectable on the WT array after extensive exposure, see Figure 2b) and downregulated in C2A on both arrays. This ®nding was essentially contrary to previous ®ndings from in vitro analyses suggesting repression of ODC by WT1 (Moshier et al, 1996;Li et al, 1999), but the change was less than twofold and in some instances WT1 can activate ODC (Moshier et al, 1996;Li et al, 1999). The sensitivity of the Wilms' tumour array should be questioned as murine WT1 failed to be detected in either the parental cell line or the C2A transfectant.…”

Section: Discussioncontrasting

confidence: 75%

Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1

Sim

Smith

et al. 2002

Oncogene

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The Wilms' tumour suppressor gene, WT1, encodes multiple nuclear protein isoforms, all containing four C-terminal zinc ®nger motifs. WT1 proteins can both activate and repress putative target genes in vitro, although the in vivo relevance of these putative target genes is often unveri®ed. WT1 mutations can result in Wilms' tumour and the Denys-Drash Syndrome (DDS) of infantile nephropathy, XY pseudohermaphroditism and predisposition to Wilms' tumour. We have established stable transfectants of the mouse mesonephric cell line, M15, which express WT1 harbouring a common DDS point mutation (R394W). A comparison of the expression pro®les of M15 and transfectant C2A was performed using Nylon-based arrays. Very few genes showed di erential expression. However Wnt-4, a member of the Wnt gene family of secreted glycoproteins, was downregulated in C2A and other similar clones. Doxycycline induction of WT1-A or WT1-D expression in HEK293 stable transfectants also elicited an elevation in Wnt4 expression. Wnt4 is critical for the mesenchyme-to-epithelial transition during kidney development, making it an attractive putative WT1 target. We have mapped human Wnt-4 gene to chromosome 1p35-36, a region of frequent LOH in WT, have characterized the genomic structure of the human Wnt-4 gene and isolated 9 kb of immediate promoter. While several potential WT1 binding sites exist within this promoter, reporter analysis does not strongly support the direct regulation of Wnt4 by WT1. We propose that Wnt-4 regulation by WT1 occurs at a more distant promoter or enhancer site, or is indirect.

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Section: Discussioncontrasting

confidence: 75%

Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1

Sim

Smith

et al. 2002

Oncogene

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“…Although c-myc has previously been shown to be repressed by WT1 (Hewitt et al, 1995), studies have shown that WT1 can either activate or repress GC-rich promoter reporters, depending on experimental conditions (Reddy et al, 1995a). In fact, WT1-A has been reported to activate or repress the ODC promoter depending on the cell line used (Moshier et al, 1996;Li et al, 1999). Amphiregulin and podocalyxin, both recently identified as WT1 target genes (Lee et al, 1999;Palmer et al, 2001), were not present on either the OCI or SRC arrays.…”

Section: Expression Profiling For Wt1-responsive Genesmentioning

confidence: 97%

Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1

et al. 2004

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“…51) is reported to be negatively regulated by WT1. 52 If WT1 blocks the proliferation of progenitor cells, how then can WT1 contribute to leukemogenesis? The answer could be that the transformation process, including several oncogenic events, includes a selection against the anti-proliferative effects of WT1 making it possible for WT1 to co-operate with certain oncogene products and to interfere with differentiation.…”

Section: Figurementioning

confidence: 99%

Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells

2001

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The Wilms tumor gene (WT1) encodes a zinc-finger containing transcription factor present in primitive hematopoietic progenitor cells. WT1 is also highly expressed in most cases of acute myeloid leukemia. Moreover, WT1 can interfere with induced differentiation of leukemic cell lines. These data suggest a function of WT1 in the maintenance of a primitive phenotype and a role in leukemogenesis by interfering with differentiation, prompting us to investigate its function in human hematopoietic progenitor cells. By retroviral transfer, human CD34 + cord blood progenitor cells were transduced with a vector encoding either of two splicing variants of WT1, with or without the KTS insert in the zinc-finger domain, linked to expression of green fluorescent protein (GFP) via an internal ribosomal entry site. When compared to cells transduced with vector containing GFP only, WT1 expressing cells showed strongly reduced colony formation in methylcellulose and inhibited proliferation in suspension culture, with no apparent reduction in viability. Cell cycle phase distribution was not affected by WT1 expression. No signs of impaired differentiation, as judged by the surface markers CD11b, CD14 and glycophorin were detected. In contrast to the results with human CD34 + progenitor cells, the proliferation of murine bone marrow cells was not significantly affected by WT1, consistent with previous data. We conclude that forced expression of WT1 in highly enriched human hematopoietic progenitor cells leads to strong anti-proliferative effects but is compatible with induced maturation of these cells. Leukemia (2001Leukemia ( ) 15, 1914Leukemia ( -1922

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Ornithine Decarboxylase Is a Transcriptional Target of Tumor Suppressor WT1

Cited by 25 publications

References 49 publications

Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1

Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1

Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1

Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells

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