The H19 Transcript Is Associated with Polysomes and May Regulate IGF2 Expression in trans

Li, Yiming; Franklin, Gary; Cui, Hengmi; Svensson, Kristian; He, Xianli; Adam, Gail; Ohlsson, Rolf; Pfeifer, Susan

doi:10.1074/jbc.273.43.28247

Cited by 101 publications

(68 citation statements)

References 26 publications

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“…However, this notion of`oncofetal RNA' de®nes the pattern of H19 expression rather than bringing any knowledge about the accurate function of the gene. Recently, Li et al (1998) reexamined a putative role for H19 transcript in humans and their observations were consistent with a H19 antagonist role to IGF2 expression in trans and could represent a ®rst approach to clarify this unsolved issue.…”

Section: Introductionmentioning

confidence: 75%

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Steroid hormones modulate H19 gene expression in both mammary gland and uterus

et al. 1999

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H19 is an imprinted and developmentally regulated gene whose product remains apparently untranslated. In a previous study on breast adenocarcinomas, we reported that overexpression of the H19 gene was signi®cantly correlated with the presence of steroid receptors, suggesting the putative role of hormones in H19 transcription. To determine the mode of steroid action, we have detected levels of H19 RNA synthesis during mammary gland development by in situ hybridization (ISH): two peaks of H19 transcription occur during puberty and pregnancy. Furthermore, we demonstrated by ISH that in the uterus H19 RNA synthesis is high during estrus and metestrus phases. To test steroid control of H19 transcription, ovariectomized and adrenalectomized mice were supplemented, 1 week after surgery, with 17-b-estradiol (E2, 20 mg/kg/day), progesterone (P, 1 mg/kg/day) or corticosterone (B, 0.3 mg/ kg/day) for 2 weeks. According to ISH data, E2 and to a lesser extent B stimulated H19 transcription in the uterus, whereas P inhibited it. To con®rm the in vivo results, in vitro experiments were performed using cultures of MCF-7 cells (a hormone-sensitive mammary cell line). E2 stimulated the endogenous H19 gene of this cell line and tamoxifen inhibited this e ect. Furthermore, we performed transient cotransfections in MCF-7, in HBL-100 (another hormone-sensitive mammary cell line) and in BT-20 (a hormone-insensitive mammary cell line) with various constructs of ERa (WT or mutated) and PR-A, in presence or absence of steroid hormones. We demonstrated that ERa up-regulated the H19 promoter in MCF-7 and in HBL-100, whereas PR-A did not have any e ect per se. Moreover, in MCF-7, PR-A antagonized clearly the ERa-mediated promoter enhancement, but in HBL-100 this counteracting e ect on the ERa up-regulation was not found. Interestingly, the same experiments performed in BT-20 cell line provided very similar results as those obtained in MCF-7 cells, with a clear down-regulation mediated by PR-A on the H19 promoter. All these in vitro data are in agreement with in vivo results. In addition, data obtained with ERa mutants indicate that H19 promoter activation is both ligand-dependent and ligand-independent. We have thus demonstrated that H19 gene expression is controlled by steroid hormones; furthermore, this gene is highly expressed in hormone-sensitive organs when the hormonal stimulation is accompanied with a morphological repair.

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Section: Introductionmentioning

confidence: 75%

“…As a consequence, it has been proposed that this gene could act as a`riboregulator' (Brannan et al, 1990). Recently, Li et al (1998) proposed that H19 RNA is associated with polysomes and modulates the cytoplasmic level of IGF2 mRNAs.…”

Section: Introductionmentioning

confidence: 99%

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

et al. 1999

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“…Using a hepatoblastoma cell line disomic for chromosome 11, Wilkin et al showed that transgenic expression of H19 antisense transcripts resulted in increased IGF2 mRNA and protein expression, whereas expression of H19 sense transgenes resulted in IGF2 transcript and protein levels equivalent to control cells (26). The level of H19 RNAs in Wilms' tumor is also found to inversely correlate with levels of IGF2 mRNA (27). In this study, H19 RNAs were found in polysomes, indicative of H19 translation and/or potential transregulation of IGF2 translation.…”

Section: Introductionmentioning

confidence: 90%

“…A role for noncoding RNAs is implicated in the regulation of imprinted genes due to the preponderance of these transcribed sequences located in imprinted domains and empirical data suggesting their importance (26,27,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). For example, the genes Delta, Drosophila homologue-like 1 (DLK1) and maternally expressed gene 3 (MEG3) in the imprinted domain on human chromosome 14 bear remarkable similarity to the IGF2/H19 domain in terms of the genomic organization and putative regulatory features (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

“…H19 has been implicated previously in the negative regulation of IGF2 and has been proposed to function as a tumor suppressor (26,27). We therefore analyzed the expression level of H19 and compared it with that of IGF2 to determine if there was any correlation between transcript levels of these genes in serous epithelial ovarian malignancies.…”

Section: H19 Expressionmentioning

confidence: 99%

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Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Murphy

Huang

Wen

et al. 2006

Molecular Cancer Research

125

103

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Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner. (Mol Cancer Res 2006;4(4):283 -92)

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ImprintedH19 gene expression in embryogenesis and human cancer: The oncofetal connection

2000

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Cancer cells resemble embryonal cells morphologically and share with them characteristics such as reduced differentiation, rapid proliferation rate, and increased motility. Genes expressed in embryogenesis, down-regulated with tissue maturation and reexpressed in cancer, are designated as oncofetal genes, and many of them are used as tumor markers. The H19 gene is an imprinted gene that is expressed from the maternal allele and functions as an RNA molecule. It is abundantly expressed in fetal life and down-regulated postnatally. We have shown oncofetal expression of H19 in human cancer. The study of H19 expression in testicular germ cell tumors of adolescents and young adults, which follow lines of differentiation of the conceptus, demonstrates dissociation between level of expression and monoallelic versus biallelic expression, which are two independent oncofetal characteristics of cancer. Expression of the maternally expressed H19 from the paternal allele in the villous cytotrophoblastic cells of the androgenetic complete hydatidiform mole is designated relaxation of imprinting. H19 is abundantly expressed in the fetal bladder mucosa and in carcinoma of the urinary bladder. It is a marker of early recurrence and may be used as a potential basis for gene therapy.

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The H19 Transcript Is Associated with Polysomes and May Regulate IGF2 Expression in trans

Cited by 101 publications

References 26 publications

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

ImprintedH19 gene expression in embryogenesis and human cancer: The oncofetal connection

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