The Experts below are selected from a list of 471651 Experts worldwide ranked by ideXlab platform
Jean Jacques Curgy - One of the best experts on this subject based on the ideXlab platform.
-
a novel H19 antisense rna overexpressed in breast cancer contributes to paternal igf2 expression
Molecular and Cellular Biology, 2008Co-Authors: Nathalie Berteaux, Jean Coll, Thierry Dugimont, Hubert Hondermarck, Nathalie Aptel, Guy Cathala, Celine Genton, Anthony Daccache, Nathalie Spruyt, Jean Jacques CurgyAbstract:The H19/IGFf2 locus belongs to a large imprinted domain located on human chromosome 11p15.5 (homologue to mouse distal chromosome 7). The H19 Gene is expressed from the maternal allele, while IGF2 is paternally expressed. Natural antisense transcripts and intergenic transcription have been involved in many aspects of eukaryotic Gene expression, including genomic imprinting and RNA interference. However, apart from the identification of some IGF2 antisense transcripts, few data are available on that topic at the H19/IGF2 locus. We identify here a novel transcriptional activity at both the human and the mouse H19/IGF2 imprinted loci. This activity occurs antisense to the H19 Gene and has the potential to produce a single 120-kb transcript that we called the 91H RNA. This nuclear and short-lived RNA is not imprinted in mouse but is expressed predominantly from the maternal allele in both mice and humans within the H19 Gene region. Moreover, the transcript is stabilized in breast cancer cells and overexpressed in human breast tumors. Finally, knockdown experiments showed that, in humans, 91H, rather than affecting H19 expression, regulates IGF2 expression in trans.
-
hormonal regulation of H19 Gene expression in prostate epithelial cells
Journal of Endocrinology, 2004Co-Authors: Nathalie Berteaux, Severine Lottin, Eric Adriaenssens, Jean Coll, Thierry Dugimont, F Van Coppenolle, X Leroy, Jean Jacques CurgyAbstract:The H19 Gene is transcribed in an mRNA-like noncoding RNA. When tumors of various organs or cell types are considered, H19 oncoGene or tumor-suppressor status remains controversial. To address the potential regulation of H19 Gene expression by an androgen steroid hormone (DHT: dihydrotestosterone) or by a peptidic hormone (PRL: prolactin), we performed experiments in rats systemically treated with chemical mediators. This range of in vivo experiments demonstrated that chronic hyperprolactinemia upregulated the H19 expression in epithelial and stromal cells whereas DHT downregulated the Gene. PRL and DHT appeared to be opposite mediators in the H19 RNA synthesis. We investigated these hormonal effects in three human prostate epithelial cell lines. In LNCaP cancer cells, the opposite effect of PRL and DHT was corroborated. However, in normal cells (PNT1A), H19 remained insensitive to the hormones in fetal calf serum (FCS) medium but became responsive in a serum-stripped medium. In the DU-145 cancer cell line, tested for its androgen-independence and aggressiveness, the hormones had no effect on H19 expression whatever the culture conditions. Finally, we demonstrated that PRL upregulated the H19 expression in LNCaP cells by the JAK2-STAT5 transduction pathway. We conclude that H19 expression is regulated by both a peptidic and a male steroid hormone.
-
overexpression of an ectopic H19 Gene enhances the tumorigenic properties of breast cancer cells
Carcinogenesis, 2002Co-Authors: Severine Lottin, Eric Adriaenssens, Thierry Dupressoir, Nathalie Berteaux, Claire Montpellier, Jean Coll, Thierry Dugimont, Jean Jacques CurgyAbstract:The maternally expressed H19 Gene is transcribed as an untranslated RNA that serves as a riboregulator. We have previously reported that this transcript accumulates in epithelial cells in approximately 10% of breast cancers. To gain further insight on how the overexpression of the H19 Gene affects the phenotype of human breast epithelial cells, we investigated the oncogenic potential of RNA that was abundantly expressed from MDA-MB-231 breast cancer cells stably transfected with the genomic sequence of the human H19 Gene. The amount of H19 RNA did not affect cell proliferation capacity, timing of cell cycle phases or anchorage-dependent ability of H19-transfected clones in vitro. But in anchorage-independent growth assays the H19-recombined cells formed more and larger colonies in soft-agar versus control cells. To explore this phenotypic change, we analysed tumour development after subcutaneous injection of H19-recombined cells into scid mice. Results showed that H19 overexpression promotes tumour progression. These data support the hypothesis that an overload of H19 transcript is associated with cells exhibiting higher tumorigenic phenotypes and therefore we conclude that the H19 Gene has oncogenic properties in breast epithelial cells.
-
overexpression of an ectopic H19 Gene enhances the tumorigenic properties of breast cancer cells
Carcinogenesis, 2002Co-Authors: Severine Lottin, Eric Adriaenssens, Thierry Dupressoir, Nathalie Berteaux, Claire Montpellier, Jean Coll, Thierry Dugimont, Jean Jacques CurgyAbstract:The maternally expressed H19 Gene is transcribed as an untranslated RNA that serves as a riboregulator. We have previously reported that this transcript accumulates in epithelial cells in ∼10% of breast cancers. To gain further insight on how the overexpression of the H19 Gene affects the phenotype of human breast epithelial cells, we investigated the oncogenic potential of RNA that was abundantly expressed from MDA-MB-231 breast cancer cells stably transfected with the genomic sequence of the human H19 Gene. The amount of H19 RNA did not affect cell proliferation capacity, timing of cell cycle phases or anchorage-dependent ability of H19-transfected clones in vitro. But in anchorage-independent growth assays the H19-recombined cells formed more and larger colonies in soft-agar versus control cells. To explore this phenotypic change, we analysed tumour development after subcutaneous injection of H19-recombined cells into scid mice. Results showed that H19 overexpression promotes tumour progression. These data support the hypothesis that an overload of H19 transcript is associated with cells exhibiting higher tumorigenic phenotypes and therefore we conclude that the H19 Gene has oncogenic properties in breast epithelial cells.
-
steroid hormones modulate H19 Gene expression in both mammary gland and uterus
Oncogene, 1999Co-Authors: Eric Adriaenssens, Severine Lottin, Jean Coll, Thierry Dugimont, W Fauquette, J P Dupouy, B Boilly, Jean Jacques CurgyAbstract: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 significantly 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-β-estradiol (E2, 20 μg/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 confirm 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 effect. 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 ERα (WT or mutated) and PR-A, in presence or absence of steroid hormones. We demonstrated that ERα up-regulated the H19 promoter in MCF-7 and in HBL-100, whereas PR-A did not have any effect per se. Moreover, in MCF-7, PR-A antagonized clearly the ERα-mediated promoter enhancement, but in HBL-100 this counteracting effect on the ERα 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 ERα 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.
Patricia Ohana - One of the best experts on this subject based on the ideXlab platform.
-
the increasing complexity of the oncofetal H19 Gene locus functional dissection and therapeutic intervention
International Journal of Molecular Sciences, 2013Co-Authors: Imad Matouk, Nathan De-groot, Patricia Ohana, Eli Raveh, Rasha Abu Lail, Eitan Gershtain, Michal Gilon, Abraham Czerniak, Abraham HochbergAbstract:The field of the long non-coding RNA (lncRNA) is advancing rapidly. Currently, it is one of the most popular fields in the biological and medical sciences. It is becoming increasingly obvious that the majority of the human transcriptome has little or no-protein coding capacity. Historically, H19 was the first imprinted non-coding RNA (ncRNA) transcript identified, and the H19/IGF2 locus has served as a paradigm for the study of genomic imprinting since its discovery. In recent years, we have extensively investigated the expression of the H19 Gene in a number of human cancers and explored the role of H19 RNA in tumor development. Here, we discuss recently published data from our group and others that provide further support for a central role of H19 RNA in the process of tumoriGenesis. Furthermore, we focus on major transcriptional modulators of the H19 Gene and discuss them in the context of the tumor-promoting activity of the H19 RNA. Based on the pivotal role of the H19 Gene in human cancers, we have developed a DNA-based therapeutic approach for the treatment of cancers that have upregulated levels of H19 expression. This approach uses a diphtheria toxin A (DTA) protein expressed under the regulation of the H19 promoter to treat tumors with significant expression of H19 RNA. In this review, we discuss the treatment of four cancer indications in human subjects using this approach, which is currently under development. This represents perhaps one of the very few examples of an existing DNA-based therapy centered on an lncRNA system. Apart from cancer, H19 expression has been reported also in other conditions, syndromes and diseases, where deregulated imprinting at the H19 locus was obvious in some cases and will be summarized below. Moreover, the H19 locus proved to be much more complicated than initially thought. It houses a genomic sequence that can transcribe, yielding various transcriptional outputs, both in sense and antisense directions. The major transcriptional outputs of the H19 locus are presented here.
-
phase i ii marker lesion study of intravesical bc 819 dna plasmid in H19 over expressing superficial bladder cancer refractory to bacillus calmette guerin
The Journal of Urology, 2008Co-Authors: Abraham Ami Sidi, Patricia Ohana, Shalva Benjamin, Moshe Shalev, Janet H Ransom, Donald L Lamm, A Hochberg, Ilan LeibovitchAbstract:Purpose: We studied the safety and preliminary efficacy (marker tumor ablation) of 5 doses of BC-819 given as 6 intravesical infusions in patients with superficial bladder cancer in whom intravesical therapy with bacillus Calmette-Guerin had failed. BC-819 is a DNA plasmid that contains H19 Gene regulatory sequences that drive the expression of an intracellular toxin.Materials and Methods: A total of 18 patients in 4 groups of 3 and 1 group of 6 received escalating doses of BC-819 intravesically during 7 weeks. Patients had low grade superficial bladder cancer, which expressed H19. The effect on a marker tumor was examined 12 weeks after starting treatment. The escalating doses were 2, 4, 6, 12 and 20 mg plasmid per intravesical treatment. Responders continued to receive BC-819 once monthly every month for 1 year.Results: No dose limiting toxicity was observed. The most frequent adverse events were mild to moderate bladder discomfort, dysuria, micturition urgency, urinary tract infection, diarrhea, hypert...
-
oncofetal splice pattern of the human H19 Gene
Biochemical and Biophysical Research Communications, 2004Co-Authors: Imad Matouk, Tamar Schneider, Abraham Hochberg, Suhail Ayesh, Patricia Ohana, Basim M Ayesh, Nathan Degroot, Eithan GalunAbstract:H19 is an imprinted Gene that demonstrates maternal monoallelic expression in fetal tissues and in some cancers, and very likely does not code for a protein. H19 is involved in the regulation of cell proliferation, embryonic growth, and differentiation through upstream and downstream cis elements that influence the expression of IGF2, a closely physically linked Gene, and also through its RNA involved in metastasis and angiogenic processes. We report the identification of an alternatively spliced variant of H19 RNA that lacks part of exon 1. This variant was detected in human embryonic and placental tissues, but not in bladder or hepatocellular carcinomas. A very low level of this variant was also detected in colon carcinoma. The observed pattern of expression suggests that this splice variant is a developmentally regulated H19 Gene transcript.
-
regulatory sequences of the H19 Gene in dna based therapy of bladder cancer
2004Co-Authors: Patricia Ohana, Tamar Schneider, Nathan De-groot, Suhail Ayesh, Imad Matouk, Tatiana Birman, A Mizrahi, Ofer N Gofrit, Wasif Alsharef, Ami A SidiAbstract:Summary The objective of the present study was to develop novel DNA based therapy strategies for bladder cancer. We detected a high expression level of the H19 Gene in murine and human bladder carcinoma tissues compared to nearly undetectable levels in the surrounding normal tissues. On the basis of these findings we constructed a plasmid in which H19 regulatory sequences drove the expression of the diphtheria toxin A Gene. This plasmid was introduced by intravesical instillation into the bladders of rats with bladder carcinoma (orthotopic model) and into the bladders of two human patients suffering recurrent superficial transitional cell carcinoma, refractory to all commonly used treatments. Very significant tumor growth inhibition was observed in the rat bladder tumors after two intravesical injections of 50 μg of DTA-H19 toxin vector as compared to control animals. Nearly complete ablation of the tumor was determined by video imaging in the two human patients after treating once a week with 2 mg of DTA-H19 plasmid for a total of 9 weeks. Not even a trace of the plasmid could be detected in the bloodstream of the patients. This observation strongly indicates the safety of our treatment. These observations may be the first step of a major breakthrough in the treatment of human bladder carcinoma.
-
Possible physiological role of H19 RNA
Molecular carcinogenesis, 2002Co-Authors: Suhail Ayesh, Tamar Schneider, Nathan De-groot, Imad Matouk, Patricia Ohana, Morris Laster, Wasif A. Al-sharef, Abraham HochbergAbstract:The product of the imprinted oncofetal H19 Gene is an untranslated RNA of unknown function. With the human cDNA Atlas microarray, we detected differentially expressed Genes modulated by the presence of H19 RNA. Many of the Genes that are upregulated by H19 RNA are known to contribute to the invasive, migratory, and angiogenic capacities of cells. Moreover, we provided experimental data indicating that whereas H19 RNA did not have any growth advantage for the cells when cultured in 10% fetal calf serum, it did confer an advantage when cells were cultured in serum-poor medium. This observation can be explained in part by the inability of the H19-expressing cells to induce the cyclin-dependent kinase inhibitor p57kip2 in response to serum stress. Our results favor the possible role of the H19 Gene in promoting cancer progression, angioGenesis, and metastasis. © 2002 Wiley-Liss, Inc.
Tamar Schneider - One of the best experts on this subject based on the ideXlab platform.
-
oncofetal splice pattern of the human H19 Gene
Biochemical and Biophysical Research Communications, 2004Co-Authors: Imad Matouk, Tamar Schneider, Abraham Hochberg, Suhail Ayesh, Patricia Ohana, Basim M Ayesh, Nathan Degroot, Eithan GalunAbstract:H19 is an imprinted Gene that demonstrates maternal monoallelic expression in fetal tissues and in some cancers, and very likely does not code for a protein. H19 is involved in the regulation of cell proliferation, embryonic growth, and differentiation through upstream and downstream cis elements that influence the expression of IGF2, a closely physically linked Gene, and also through its RNA involved in metastasis and angiogenic processes. We report the identification of an alternatively spliced variant of H19 RNA that lacks part of exon 1. This variant was detected in human embryonic and placental tissues, but not in bladder or hepatocellular carcinomas. A very low level of this variant was also detected in colon carcinoma. The observed pattern of expression suggests that this splice variant is a developmentally regulated H19 Gene transcript.
-
regulatory sequences of the H19 Gene in dna based therapy of bladder cancer
2004Co-Authors: Patricia Ohana, Tamar Schneider, Nathan De-groot, Suhail Ayesh, Imad Matouk, Tatiana Birman, A Mizrahi, Ofer N Gofrit, Wasif Alsharef, Ami A SidiAbstract:Summary The objective of the present study was to develop novel DNA based therapy strategies for bladder cancer. We detected a high expression level of the H19 Gene in murine and human bladder carcinoma tissues compared to nearly undetectable levels in the surrounding normal tissues. On the basis of these findings we constructed a plasmid in which H19 regulatory sequences drove the expression of the diphtheria toxin A Gene. This plasmid was introduced by intravesical instillation into the bladders of rats with bladder carcinoma (orthotopic model) and into the bladders of two human patients suffering recurrent superficial transitional cell carcinoma, refractory to all commonly used treatments. Very significant tumor growth inhibition was observed in the rat bladder tumors after two intravesical injections of 50 μg of DTA-H19 toxin vector as compared to control animals. Nearly complete ablation of the tumor was determined by video imaging in the two human patients after treating once a week with 2 mg of DTA-H19 plasmid for a total of 9 weeks. Not even a trace of the plasmid could be detected in the bloodstream of the patients. This observation strongly indicates the safety of our treatment. These observations may be the first step of a major breakthrough in the treatment of human bladder carcinoma.
-
Possible physiological role of H19 RNA
Molecular carcinogenesis, 2002Co-Authors: Suhail Ayesh, Tamar Schneider, Nathan De-groot, Imad Matouk, Patricia Ohana, Morris Laster, Wasif A. Al-sharef, Abraham HochbergAbstract:The product of the imprinted oncofetal H19 Gene is an untranslated RNA of unknown function. With the human cDNA Atlas microarray, we detected differentially expressed Genes modulated by the presence of H19 RNA. Many of the Genes that are upregulated by H19 RNA are known to contribute to the invasive, migratory, and angiogenic capacities of cells. Moreover, we provided experimental data indicating that whereas H19 RNA did not have any growth advantage for the cells when cultured in 10% fetal calf serum, it did confer an advantage when cells were cultured in serum-poor medium. This observation can be explained in part by the inability of the H19-expressing cells to induce the cyclin-dependent kinase inhibitor p57kip2 in response to serum stress. Our results favor the possible role of the H19 Gene in promoting cancer progression, angioGenesis, and metastasis. © 2002 Wiley-Liss, Inc.
-
Use of H19 regulatory sequences for targeted Gene therapy in cancer
International Journal of Cancer, 2002Co-Authors: Patricia Ohana, Tamar Schneider, Ilana Ariel, Suhail Ayesh, Imad Matouk, Tatiana Birman, Osaat Bibi, Carol Levy, Hilla Giladi, Morris LasterAbstract:We present a tumor Gene therapy approach based on the use of regulatory sequences of the H19 Gene that are differentially expressed between normal and cancer cells. We constructed expression vectors carrying the Gene for the A fragment of diphtheria toxin (DT-A) or herpes simplex virus thymidine kinase (HSV-tk), under the control of a 814 bp 5′-flanking region of the H19 Gene. The cell killing activity of these constructs was in accordance with the relative activity of the H19 regulatory sequences in the transfected cells. We evaluated the therapeutic potential of the Gene expression constructs driven by H19 regulatory sequences in an animal model of bladder cancer induced by subcutaneous injection of synGeneic bladder tumor cell lines. Intratumoral injection of these constructs caused a significant suppression of subcutaneous tumor growth, with no obvious toxicity toward the host. © 2002 Wiley-Liss, Inc.
-
the expression of the H19 Gene and its function in human bladder carcinoma cell lines
FEBS Letters, 1999Co-Authors: Patricia Ohana, Tamar Schneider, Suhail Ayesh, E Kopf, O Bibi, Mark L Tykocinski, N De Groot, A HochbergAbstract:The human H19 Gene is a paternally imprinted oncofetal Gene, highly expressed in several fetal tissues, down-regulated in nearly all adult tissues but re-expressed in carcinomas of tissues which express the Gene in fetal life. It has no known protein product and till today, no function could be designated to H19 RNA. Cells derived from bladder carcinomas and hepatocellular carcinomas were transfected with plasmids carrying a luciferase reporter Gene under the control of a 800 nucleotides long promoter region of the H19 Gene either alone or together with different parts of a 5 kb downstream region, previously shown to possess enhancer activity. Our results provide evidence that three regions of the 3′ downstream sequence can independently stimulate the H19 promoter activity in a tissue and cell specific manner. The growth rate of two cell populations, both derived from the same bladder carcinoma cell line and which differ in their H19 RNA content, were compared. The cells with a high H19 RNA level stopped their proliferation after 48 h when cultivated in a low serum containing media while the cells lacking H19 RNA continued their proliferation for at least an additional 48 h period.
Abraham Hochberg - One of the best experts on this subject based on the ideXlab platform.
-
the increasing complexity of the oncofetal H19 Gene locus functional dissection and therapeutic intervention
International Journal of Molecular Sciences, 2013Co-Authors: Imad Matouk, Nathan De-groot, Patricia Ohana, Eli Raveh, Rasha Abu Lail, Eitan Gershtain, Michal Gilon, Abraham Czerniak, Abraham HochbergAbstract:The field of the long non-coding RNA (lncRNA) is advancing rapidly. Currently, it is one of the most popular fields in the biological and medical sciences. It is becoming increasingly obvious that the majority of the human transcriptome has little or no-protein coding capacity. Historically, H19 was the first imprinted non-coding RNA (ncRNA) transcript identified, and the H19/IGF2 locus has served as a paradigm for the study of genomic imprinting since its discovery. In recent years, we have extensively investigated the expression of the H19 Gene in a number of human cancers and explored the role of H19 RNA in tumor development. Here, we discuss recently published data from our group and others that provide further support for a central role of H19 RNA in the process of tumoriGenesis. Furthermore, we focus on major transcriptional modulators of the H19 Gene and discuss them in the context of the tumor-promoting activity of the H19 RNA. Based on the pivotal role of the H19 Gene in human cancers, we have developed a DNA-based therapeutic approach for the treatment of cancers that have upregulated levels of H19 expression. This approach uses a diphtheria toxin A (DTA) protein expressed under the regulation of the H19 promoter to treat tumors with significant expression of H19 RNA. In this review, we discuss the treatment of four cancer indications in human subjects using this approach, which is currently under development. This represents perhaps one of the very few examples of an existing DNA-based therapy centered on an lncRNA system. Apart from cancer, H19 expression has been reported also in other conditions, syndromes and diseases, where deregulated imprinting at the H19 locus was obvious in some cases and will be summarized below. Moreover, the H19 locus proved to be much more complicated than initially thought. It houses a genomic sequence that can transcribe, yielding various transcriptional outputs, both in sense and antisense directions. The major transcriptional outputs of the H19 locus are presented here.
-
oncofetal splice pattern of the human H19 Gene
Biochemical and Biophysical Research Communications, 2004Co-Authors: Imad Matouk, Tamar Schneider, Abraham Hochberg, Suhail Ayesh, Patricia Ohana, Basim M Ayesh, Nathan Degroot, Eithan GalunAbstract:H19 is an imprinted Gene that demonstrates maternal monoallelic expression in fetal tissues and in some cancers, and very likely does not code for a protein. H19 is involved in the regulation of cell proliferation, embryonic growth, and differentiation through upstream and downstream cis elements that influence the expression of IGF2, a closely physically linked Gene, and also through its RNA involved in metastasis and angiogenic processes. We report the identification of an alternatively spliced variant of H19 RNA that lacks part of exon 1. This variant was detected in human embryonic and placental tissues, but not in bladder or hepatocellular carcinomas. A very low level of this variant was also detected in colon carcinoma. The observed pattern of expression suggests that this splice variant is a developmentally regulated H19 Gene transcript.
-
Possible physiological role of H19 RNA
Molecular carcinogenesis, 2002Co-Authors: Suhail Ayesh, Tamar Schneider, Nathan De-groot, Imad Matouk, Patricia Ohana, Morris Laster, Wasif A. Al-sharef, Abraham HochbergAbstract:The product of the imprinted oncofetal H19 Gene is an untranslated RNA of unknown function. With the human cDNA Atlas microarray, we detected differentially expressed Genes modulated by the presence of H19 RNA. Many of the Genes that are upregulated by H19 RNA are known to contribute to the invasive, migratory, and angiogenic capacities of cells. Moreover, we provided experimental data indicating that whereas H19 RNA did not have any growth advantage for the cells when cultured in 10% fetal calf serum, it did confer an advantage when cells were cultured in serum-poor medium. This observation can be explained in part by the inability of the H19-expressing cells to induce the cyclin-dependent kinase inhibitor p57kip2 in response to serum stress. Our results favor the possible role of the H19 Gene in promoting cancer progression, angioGenesis, and metastasis. © 2002 Wiley-Liss, Inc.
-
imprinted H19 Gene expression in embryoGenesis and human cancer the oncofetal connection
American Journal of Medical Genetics, 2000Co-Authors: I Ariel, Nathan De-groot, Abraham HochbergAbstract: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.
-
The imprinted H19 Gene as a tumor marker in bladder carcinoma
Urology, 1995Co-Authors: Ilana Ariel, Tamar Schneider, Nathan De-groot, Galina Pizov, O. Lustig, Mally Sappir, Abraham HochbergAbstract:Abstract Objectives. Genomic imprinting is a newly discovered mechanism in Genetics that is involved in tumoriGenesis. H19 is an imprinted Gene in the human, expressed from the maternal allele. It is extensively transcribed in fetal life but is not translated and functions as an RNA molecule. It has been suggested as a candidate tumor suppressor Gene. We studied the expression of H19 in human cancer arising from tissues expressing H19 fetal life, one of which is bladder mucosa. Methods. In situ hybridization for H19 mRNA on paraffin sections of bladder carcinoma in different histologic grades. Results. Low-grade (grade 1 of 3), noninvasive (Ta) papillary transitional cell bladder carcinoma did not express H19, but prominent expression was disclosed in higher grades, invasive transitional cell carcinomas (T1-T3/4). Expression was also evident in in situ bladder carcinoma (Tis), which tends to progress rapidly to invasive cancer. Conclusions. We suggest that H19 can be used as a tumor marker in human bladder carcinoma, where its expression indicates a more malignant potential.
Shirley M Tilghman - One of the best experts on this subject based on the ideXlab platform.
-
igf2 imprinting does not require its own dna methylation or H19 rna
Genes & Development, 1998Co-Authors: Beverly K Jones, John Levorse, Shirley M TilghmanAbstract:Three models have been proposed to explain the imprinting of the mouse Igf2 Gene on the maternal chromosome. We ruled out the importance of DNA methylation at Igf2 by showing that silencing of Igf2 accompanying the loss of DNA methylation could be overcome by a mutation at the neighboring H19 Gene that activates Igf2. By replacing the H19 structural Gene with a protein-coding Gene, we have ruled out a role for H19 RNA in the imprinting of Igf2. This replacement resulted in sporadic activation of the H19 promoter on the paternal chromosome without affecting the level of expression of Igf2, a finding that is inconsistent with strict promoter competition between the Genes. We conclude that a transcriptional model involving access to a common set of enhancers shared between Igf2 and H19 is the most likely explanation for Igf2 imprinting.
-
structure and expression of the mouse l23mrp Gene downstream of the imprinted H19 Gene biallelic expression and lack of interaction with the H19 enhancers
Genomics, 1997Co-Authors: Mohamad Zubair, Azim M Surani, Shirley M Tilghman, Kathy Hilton, Jennifer R Saam, Hiroyuki SasakiAbstract:The human L23 (mitochondrial)-related protein Gene, located 40 kb downstream of the imprinted H19 Gene, is biallelically expressed. We have cloned and characterized its mouse homolog, L23mrp, which maps to the conserved syntenic region on mouse chromosome 7. The promoter of L23mrp is a CpG island that is transcribed ubiquitously, but at different levels, in different fetal tissues. Allele-specific expression analysis revealed that both parental alleles are equally active. Since the enhancers located between H19 and L23mrp had been shown to be involved in the imprinted expression of Ins-2, Igf-2, and H19, we asked whether they also influence L23mrp. Analysis of mice with a targeted deletion of the enhancers demonstrated that they were not disrupted in the expression of L23mrp. These findings indicate that L23mrp is functionally insulated from the Ins-2/Igf-2/H19 domain in terms of both imprinting and enhancer action.
-
loss of the maternal H19 Gene induces changes in igf2 methylation in both cis and trans
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: T Forne, Shirley M Tilghman, L. Dandolo, J Oswald, Wendy Dean, J R Saam, B Bailleul, Jorn Walter, Wolf ReikAbstract:Recent investigations have shown that the maintenance of genomic imprinting of the murine insulin-like growth factor 2 (Igf2) Gene involves at least two factors: the DNA (cytosine-5-)-methyltransferase activity, which is required to preserve the paternal specific expression of Igf2, and the H19 Gene (lying 90 kb downstream of Igf2 Gene), which upon inactivation leads to relaxation of the Igf2 imprint. It is not yet clear how these two factors are related to each other in the process of maintenance of Igf2 imprinting and, in particular, whether the latter is acting through cis elements or whether the H19 RNA itself is involved. By using Southern blots and the bisulfite genomic-sequencing technique, we have investigated the allelic methylation patterns (epigenotypes) of the Igf2 Gene in two strains of mouse with distinct deletions of the H19 Gene. The results show that maternal transmission of H19 Gene deletions leads the maternal allele of Igf2 to adopt the epigenotype of the paternal allele and indicate that this phenomenon is influenced directly or indirectly by the H19 Gene expression. More importantly, the bisulfite genomic-sequencing allowed us to show that the methylation pattern of the paternal allele of the Igf2 Gene is affected in trans by deletions of the active maternal allele of the H19 Gene. Selection during development for the appropriate expression of Igf2, dosage-dependent factors that bind to the Igf2 Gene, or methylation transfer between the parental alleles could be involved in this trans effect.
-
the structural H19 Gene is required for transGene imprinting
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Karl Pfeifer, Philip A Leighton, Shirley M TilghmanAbstract:The product of the H19 Gene is an untranslated RNA that is expressed exclusively from the maternal chromosome during mammalian development. The H19 Gene and its 5'-flanking sequence are required for the genomic imprinting of two paternally expressed Genes, Ins-2 (encodes insulin-2) and Igf-2 (encodes insulin-like growth factor-2), that lie 90 and 115 kb 5' to the H19 Gene, respectively. In this report, the role of the H19 Gene in its own imprinting is investigated by introducing a Mus spretus H19 Gene into heterologous locations in the mouse genome. Multiple copies of the transGene were sufficient for its paternal silencing and DNA methylation. Replacing the H19 structural Gene with a luciferase reporter Gene resulted in loss of imprinting of the transGene. That is, high expression and low levels of DNA methylation were observed upon both paternal and maternal inheritance. The removal of 701 bp at the 5' end of the structural Gene resulted in a similar loss of paternal-specific DNA methylation, arguing that those sequences are required for both the establishment and maintenance of the sperm-specific gametic mark. The M. spretus H19 transGene could not rescue the loss of Igf-2 imprinting in trans in H19 deletion mice, implying a cis requirement for the H19 Gene. In contrast to a previous report in which overexpression of a marked H19 Gene was a prenatal lethal, expression of the M. spretus transGene had no deleterious effect, leading to the conclusion that the 20-base insertion in the marked Gene created a neomorphic mutation.
-
disruption of imprinting caused by deletion of the H19 Gene region in mice
Nature, 1995Co-Authors: Philip A Leighton, Robert S Ingram, Jonathan T Eggenschwiler, Argiris Efstratiadis, Shirley M TilghmanAbstract:The imprinted H19 Gene, which encodes an untranslated RNA, lies at the end of a cluster of imprinted Genes in the mouse. Imprinting of the insulin-2 and insulin-like growth factor 2 Genes, which lie about 100 kilobases upstream of H19, can be disrupted by maternal inheritance of a targeted deletion of the H19 Gene and its flanking sequence. Animals inheriting the H19 mutation from their mothers are 27% heavier than those inheriting it from their fathers. Paternal inheritance of the disruption has no effect, which presumably reflects the normally silent state of the paternal Gene. The somatic overgrowth of heterozygotes for the maternal deletion is attributed to a gain of function of insulin-like growth factor 2, rather than a loss of function of H19.
