IGF2 is parentally imprinted during human embryogenesis and in the Beckwith–Wiedemann syndrome

Ohlsson, Rolf; Nyström, A.; Pfeifer-Ohlsson, Susan; Töhönen, Virpi; Hedborg, Fredrik; Schofield, Paul N.; Flam, Folke; Ekström, Tomas J.

doi:10.1038/ng0593-94

Cited by 262 publications

(128 citation statements)

References 17 publications

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“…Sporadic Wilms tumors without WT1 mutation frequently show loss of imprinting of IGF2 locus and many genes within this region may be deregulated (Ogawa et al, 1993). Wilms tumors are also associated with loss of imprinting of the IGF2 region in the Beckwith-Wiedemann syndrome (Ohlsson et al, 1993;Weksberg et al, 1993). Wilms tumors are generally sensitive to chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

et al. 2010

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The WTX, Wilms tumor-associated tumor-suppressor gene, is present on the X chromosome and a single WTX mutation may be sufficient to promote carcinogenesis. Unlike the WT1 tumor suppressor, a transcription factor, WTX lacks conserved functional protein domains. To study the function of WTX, we constructed inducible cell lines expressing WTX and tumor-associated WTX mutants. Induction of WTX inhibited cell growth and caused G 1 /G 0 arrest. In contrast, a short, tumorassociated truncation mutant of WTX358 only slightly inhibited cell growth without a significant cell-cycle arrest, although expression of a longer truncation mutant WTX565 led to the growth inhibition and cell-cycle arrest to a similar extent as wild-type WTX. Like WT1, WTX slowed growth and caused cell-cycle arrest through p21 induction. Gene expression profiling showed that these two tumorsuppressors regulated genes in similar pathways, including those implicated in control of the cellular growth, cell cycle, cell death, cancer and cardiovascular system development. When gene expression changes mediated by wild-type WTX were compared with those affected by mutant forms, WTX565 showed a 55% overlap (228 genes) in differentially regulated genes, whereas WTX358 regulated only two genes affected by wild-type WTX, implying that amino-acid residues 358-561 are critical for WTX function.

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Section: Introductionmentioning

confidence: 99%

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

et al. 2010

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“…IGF2 and H19 are two imprinted genes located adjacent to each other at 11p15.5, a region which is frequently involved in cancer. In the case of IGF2 gene, only the paternally inherited allele is expressed while the maternal allele is silent (Giannoukakis et al, 1993;Ohlsson et al, 1993). The H19 gene is oppositely imprinted and is expressed from only the maternal allele (Goshen et al, 1993;Zhang et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

et al. 1999

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Relaxation of IGF2 imprinting occurs in Wilms tumours and many other cancers, but the mechanism of loss of imprinting (LOI) remains unknown. To investigate the role of altered DNA methylation in LOI, we examined the pattern of methylation of the human insulin-IGF2 region in Wilms tumours and the normal kidney. The analysis included regions homologous to three`di erentially methylated regions' of the mouse Igf2 gene (dmrs 0, 1 and 2). In tumours displaying normal IGF2 imprinting, and in the normal kidney, maternal allelespeci®c DNA methylation was identi®ed spanning exons 2 and 3. This region is homologous to dmr 0, a site of maternal-speci®c di erential methylation in the mouse. In Wilms tumours with relaxed imprinting or 11p15.5 LOH this region was unmethylated. No other di erential methylation was identi®ed. In particular, two sites of paternal methylation in the mouse (dmrs 1 and 2), and all three imprinted IGF2 promoters were not methylated in the kidney or in Wilms tumours. We postulate that LOI in Wilms tumours is associated with loss of maternal allele-speci®c methylation from a region located upstream of the imprinted IGF2 promoters. This region may contain cis acting sequences that coordinately in¯uence imprinting.

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“…Nine imprinted genes have been identified in man: the insulin-like growth factor II gene (tGF2) (Ohlsson et a/., 1993;Giannoukakis et al, 1993) and its receptor gene (IGF2R) (Xu et al, 1993), H19 gene (H19) (Zang and Tycko, 1992), the p57 K~P2 gene (Hatada et al, 1996), the Wilms tumor suppressor gene (WT1) (Jinno et al, 1994), the small nuclear ribonucleoprotein-associated polypeptide N gene (SNRPN) (Oz~elik et al, 1993), and transcripts (IPW, PAR1 and PAR5) from the Prader-Willi syndrome critical region (Wevrick et al, 1994;Sutcliffe et al, 1994). Among them, IGF2, SNRPN, IPW, PARI and PAR5 are paternally expressed, and the remaining 3 are maternally expressed genes.…”

Section: Introductionmentioning

confidence: 99%

Polymorphic and tissue-specific imprinting of the human wilms tumor gene,WT1

1997

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SummaryWe previously demonstrated maternal monoaltelic expression of the Wilms tumor suppressor gene, WT1, in about half of pre-term placental villus and fetal brain tissues examined. There were two alternative explanations for this pattern of the WT1 expression, i.e., an imprinting polymorphism vs. a developmental stage-dependent switching from monoatlelic to biallelic expression of the gene. To investigate these possibilities, we examined WT1 expression in a larger number of villus samples (46 samples) with gestational ages ranging from 4 to 21 weeks, using reverse transcriptase-based polymerase chain reaction (RT-PCR) to amplify the sequences for polymorphic sites in the 3'-untranslated region (UTR) of WT1. Maternal monoallelic expression was observed in 7 (39%) of 18 samples informative for the polymorphism, while the expression of the remaining 11 samples was biallelic. In addition, there was no correlation between expression patterns and gestational ages of the samples. The results indicate that the pattern of expression (monoallelic vs. biallelic) is polymorphic. The expression patterns were also studied in five different organs from a 21-week-old fetus, showing monoallelic expression only in the placenta and biallelic expression in other organs (heart, lung, liver and intestine). The finding supports the tissue specificity of the WT1 monoallelic expression°

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IGF2 is parentally imprinted during human embryogenesis and in the Beckwith–Wiedemann syndrome

Cited by 262 publications

References 17 publications

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

Polymorphic and tissue-specific imprinting of the human wilms tumor gene,WT1

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