Imprinted expression of the Igf2r gene depends on an intronic CpG island

Wutz, Anton; Smrzka, Oskar W.; Schweifer, Norbert; Schellander, K.; Wagner, Erwin F.; Barlow, Denise P.

doi:10.1038/39631

Cited by 546 publications

(389 citation statements)

References 26 publications

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“…The literature also indicates that mutations were not found in exons 4, 6, and 7 but that polymorphisms were found in exons 4 and 7 [26]. We did not find any p73 mutations in the areas analogous to mutational hot spots in p53, but we cannot exclude that p73 mutations may occur outside these exons or in specific intron regions important in gene regulation [27,28]. Moreover, point mutations in p73 may not be the only way to abrogate or compromise p73 function.…”

Section: Mutation Of the P73 Genecontrasting

confidence: 52%

Alteration of p73 in acute myelogenous leukemia

et al. 2005

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The frequency of p73 mutation is low in hematologic malignancies as well as solid tumors. In the present study, we scanned for mutations in the exons 4, 5, 6, and 7 of p73, as well as methylation of the CpG island in the untranslated region of exon 1, in 100 de novo AML patients. Four patients showed mutation in exon 5 and one in exon 6, and none of the patients showed mutation in exons 4 and 7. None of the patients showed p73 gene methylation. The expression level of p73 mRNA was also examined in 40 AML samples using reverse transcriptase-polymerase chain reaction. Only six AML patients showed p73 mRNA expression, as analyzed by RT-PCR analysis. However, p73 over-expression in 30% of patients was demonstrated by immunocytochemistry and Western blot analysis. Further, mutation of p73 has been correlated with p73 mRNA and p73 protein status. The results show the presence of over-expressed p73 mRNA and protein in the samples with mutated p73 gene. Thus, it is presumed that mutation of p73 might lead to production of defective p73 protein and p73 mRNA, and this might have a role in the process of leukemogenesis of AML. This report is the first demonstrating the presence of mutations in p73 gene in acute myelogenous leukemia. Am.

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Section: Mutation Of the P73 Genecontrasting

confidence: 52%

Alteration of p73 in acute myelogenous leukemia

et al. 2005

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“…Second, antisense mRNAs were suggested to promote the methylation of sense mRNA promoters. And third, the formation of double-stranded RNA hybrids may interfere with further mRNA processing (Wutz et al, 1997;Lai, 2002;Prescott and Proudfoot, 2002;Tufarelli et al, 2003;Lavorgna et al, 2004;Crampton et al, 2006). These models are not mutually exclusive, and more than one of them may apply to the situation of p53 and WRAP53.…”

Section: Discussionmentioning

confidence: 99%

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Bug

Dobbelstein

2011

Oncogene

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Mutant p53 frequently accumulates in cancer cells and promotes tumor cell invasion, as part of its gain of function. Its accumulation is partially due to enhanced stability, but little is known about how the mRNA levels of mutant p53 can be regulated. Likewise, the impact of cancer therapy on the levels of mutant p53 is poorly understood. We show here that the anthracyclines doxorubicin, daunorubicin and epirubicin further increase the amounts of mutant p53 mRNA and protein in cancer cells. Moreover, we show for the first time that the transcription factor E2F1 associates with the promoter DNA of TP53. Upon genotoxic treatment, E2F1 contributed to the expression of mutant p53, both directly and through induction of TAp73. In contrast, the anthracycline idarubicin and also another topoisomerase inhibitor, etoposide, failed to increase the levels of p53 mRNA, despite their ability to induce the synthesis of TAp73 mRNA. Instead, a natural antisense transcript of TP53, WRAP53, was strongly augmented by idarubicin and etoposide, but only less so by the other anthracyclines under study. RNA corresponding to the first exon of WRAP53 was mainly found in cell nuclei and it reduced the levels of mutant p53. Taken together, this suggests a reciprocal activation pattern of TP53 and WRAP53 by different chemotherapeutics. Reducing the levels of mutant p53 by small-interfering RNA increased chemosensitivity, and idarubicin prevented cell survival more efficiently than the mutant p53-inducing doxorubicin. We conclude that even closely related anthracyclines induce the synthesis of different, opposing transcripts from the TP53 locus. When using these drugs for cancer therapy, the increased levels of mutant p53 may augment its gain of function and thus favor unwanted chemoresistance and tumor progression.

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“…A large number of studies showed a correlation between methylation status of a CpG rich promoter and the neighboring CpG islands in certain imprinted genes (Ainscough et al, 1997;Wutz et al, 1997). We next determined whether methylation of the VHL CpG island correlated with methylation (demethylation) of its neighboring CpG clusters.…”

Section: Methylation Patterns Of Sequences¯anking the Vhl Genementioning

confidence: 97%

Analysis of aberrant methylation of the VHL gene by transgenes, monochromosome transfer, and cell fusion

Kuzmin

Geil

et al. 1999

Oncogene

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Several tumor suppressor genes were shown to be inactivated by a process involving aberrant de novo methylation of their GC-rich promoters which is usually associated with transcriptional repression. The mechanisms underlying this process are poorly understood. In particular this abnormal methylation may be caused and/ or maintained by either de®ciency of some trans-acting factor(s) or by various malfunctions acting in cis. Here we studied the nature of aberrant methylation of the von Hippel-Lindau (VHL) disease tumor suppressor gene in a human clear cell renal carcinoma cell line, UOK 121, that contains a silent hypermethylated endogenous VHL allele. First, we transfected unmethylated VHL transgenes, driven by the VHL promoter, into UOK 121 cells. Next, to exclude possible position e ects that may in¯uence methylation of the introduced VHL genes, we transferred a single chromosome 3, carrying an apparently normal hypomethylated VHL allele into the UOK 121 cells. Finally, we created somatic cell hybrids between UOK 121 and UMRC 6 cells containing a mutant VHL-expressing hypomethylated allele. In these three experiments both the methylation of the VHL promoter and the transcriptional status of the introduced and endogenous VHL alleles remained unchanged. Our results demonstrate that the putative trans-acting factors present in the UOK 121 and UMRC 6 cells are unable to induce changes in methylation pattern of the VHL alleles in all cell lines and hybrids studied. Taken together, the results indicate that cis-speci®c local features are pivotal in maintaining and perpetuating aberrant methylation of the VHL CpG island. Contribution of some putative trans-acting factors cannot be excluded during a period when the aberrant VHL methylation pattern was ®rst generated.

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Imprinted expression of the Igf2r gene depends on an intronic CpG island

Cited by 546 publications

References 26 publications

Alteration of p73 in acute myelogenous leukemia

Alteration of p73 in acute myelogenous leukemia

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Analysis of aberrant methylation of the VHL gene by transgenes, monochromosome transfer, and cell fusion

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