Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ewing family tumors (EFTs) are associated with a chromosomal translocation resulting in a fusion of the amino-terminus of EWS with the DNA-binding domain of an ETS transcription factor. Although previous reports suggested that these chimeric proteins would act as aberrant transcription factors, their downstream targets have not been fully elucidated. To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line, HT-1080, by retroviral transduction. Here we report that the LAMB3 gene encoding the beta3 chain of basement membrane protein laminin-5 is induced to a significantly higher level in cells expressing EWS-ETSs than in cells expressing normal ETSs. Additionally through use of an antisense oligonucleotide for EWS-ERG in the W-ES EFT cell line, laminin beta3 protein was reduced coordinately with EWS-ERG fusion protein expression. Furthermore, we found small mRNAs were preferentially transcribed from the LAMB3 gene in EFT cell lines. Molecular cloning of the entire coding region shows that the alternative transcripts from different promoter(s) located within the intron 14, which encode small proteins, likely are major products of the LAMB3 gene in EFT cells. We show that the small isoforms conferred increased anchorage-independent proliferation to NIH3T3 cells. Together with previous studies showing that laminin-5 is involved in the invasive and malignant phenotype of several tumor types, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by upregulation of LAMB3 expression.
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PMID:Aberrant laminin beta3 isoforms downstream of EWS-ETS fusion genes in Ewing family tumors. 1590 95

Ets-1 is the prototype of the family of ETS transcription factors. In human tumors, Ets-1 is expressed in endothelial cells and fibroblasts of the tumor stroma and is proposed to play a role in tumor vascularization and invasion by upregulating expression of matrix-degrading proteases. In human carcinomas, Ets-1 is also expressed by neoplastic cells, but little is known about the functional implications of this observation. We have addressed the role of Ets-1 in epithelial HeLa tumor cells by selecting stably Ets-1 over and underexpressing HeLa cells. Ets-1 expression increases the transformed phenotype of HeLa cells, by promoting cell migration, invasion and anchorage-independent growth, while Ets-1 downregulation reduces cell attachment. In correlation with these results, Ets-1 upregulation increases integrinbeta2 expression but not that of other integrins. These results suggest that, in addition to its role in the tumor stroma, Ets-1 may also promote tumor development and progression by increasing neoplastic transformation.
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PMID:Ets-1 expression promotes epithelial cell transformation by inducing migration, invasion and anchorage-independent growth. 1594 Feb 56

The ETS gene family encodes unique transcription regulators that have a common ETS DNA binding domain. At least 25 distinct ETS related genes have been isolated from various species. The ETS family transcription factors are known to regulate genetic programs essential for differentiation and development processes and play diverse roles in a number of biological processes such as organogenesis and tissue remodelling during murine development, hematopoiesis, B-cell development, activation of T-cells and signal transduction, as well as osteogenesis, osteoblast differentiation and extracellular matrix mineralization. Based on the observation of overexpression of ETS related genes in various primary and metastatic tumors, their utility as potential therapeutic targets has been suggested. Antisense oligonucleotides, transdominant, and dominant-negative mutants have been exploited to target and inhibit ETS gene expression selectively. These ETS-targeted studies are being pursued to assess their antitumour effect, and hold the potential that such specific ETS-targeted inhibitors may become a viable option for cancer therapy. Collectively, these studies also demonstrate that Ets factors can regulate multiple aspects of the malignant phenotype of many tumor cells in particular neoangiogenesis and extracellular matrix-regulated (ECM-regulated) cell proliferation, motility and invasiveness.
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PMID:ETS transcription factors and targets in tumour invasion, angiogenesis and bone metastasis. 1599 69

The Ewing sarcoma family of tumors (ESFT) comprises morphologically heterogeneous tumors that are characterized by nonrandom chromosomal translocations involving the EWS gene and one of several members of the ETS family of transcription factors. The translocation t(11;22)(q24;q12) is the most common and leads to the formation of the EWS-FLI1 fusion protein, which contributes to ESFT pathogenesis by modulating the expression of target genes. Tumors may be composed of small uniform cells with minimal morphologic evidence of differentiation, or they may be composed of larger, less uniform cells with varying degrees of neuroectodermal differentiation. CD99 expression is identified in nearly all ESFT and constitutes a useful positive marker when used as part of a panel of immunostains that can help rule out other differential diagnostic considerations. Molecular diagnostic tests commonly used to detect the presence of ESFT-specific translocations include RT-PCR and fluorescence in situ hybridization. Current therapy for patients with ESFT includes chemotherapy and surgery with or without radiation therapy. At present, the most significant prognostic factor for patients with ESFT is whether the disease is localized or metastatic.
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PMID:Ewing sarcoma family of tumors. 1609 83

Ewing tumors, which comprise Ewing's sarcoma and peripheral primitive neuroectodermal tumors, are highly aggressive and mostly affect children and adolescents. Their molecular signature is a chromosomal translocation leading to the generation of EWS-ETS (or very rarely FUS-ETS) fusion proteins that are capable of transforming cells. These oncoproteins act as aberrant transcription factors due to the fusion of an ETS DNA binding domain to a highly potent EWS (or FUS) transactivation domain. Accordingly, many EWS-ETS target genes have been identified whose dysregulation could contribute to the development of tumor formation. Furthermore, EWS-ETS oncoproteins may impact on RNA splicing or affect other proteins through disturbing their ability to form functional complexes. The molecular knowledge gained so far from studying EWS-ETS oncoproteins has not only broadened our understanding of Ewing tumors but also improved the diagnosis of these highly undifferentiated tumors. In addition, several potential prognostic markers have been uncovered and novel therapies are suggested that may improve the still dismal survival rate of Ewing tumor patients.
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PMID:EWS-ETS oncoproteins: the linchpins of Ewing tumors. 1620 44

The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression.
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PMID:The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. 1620 64

High CD99 expression levels and rearrangements of the EWS gene with ETS transcription factor genes characterize the Ewing's sarcoma family of tumors (ESFT). CD99 is a cell surface glycoprotein whose engagement has been implicated in cell proliferation as well as upregulation and transport of several transmembrane proteins in hematopoietic cells. In ESFT, antibody ligation of CD99 induces fast homotypic cell aggregation and cell death although its functional role in these processes remains largely unknown. Here, using an RNAi approach, we studied for the first time the consequences of modulated CD99 expression in six different ESFT cell lines, representing the most frequent variant forms of EWS gene rearrangement. CD99 suppression resulted in growth inhibition and reduced migration of ESFT cells. Among genes whose expression changes in response to CD99 modulation, the potassium-channel modulatory factor KCMF1 was consistently upregulated. In a series of 22 primary ESFT, KCMF1 expression levels inversely correlated with CD99 abundancy. Cells forced to express ectopic KCMF1 showed a similar reduction in migratory ability as CD99 silenced ESFT cells. Our results suggest that in ESFT, high CD99 expression levels contribute to the malignant properties of ESFT by promoting growth and migration of tumor cells and identify KCMF1 as a potential metastasis suppressor gene downregulated by high constitutive CD99 expression in ESFT.
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PMID:Suppression of KCMF1 by constitutive high CD99 expression is involved in the migratory ability of Ewing's sarcoma cells. 1631 31

The Ets transcription factors regulate a wide variety of biologic processes. Several members have been shown to play a role in regulating angiogenesis and vascular development. For example, the Ets factor ELF-1 is enriched in the developing vasculature of the embryo, where it regulates the expression of the Tie2 gene. We have determined that ELF-1 and Tie2 expression is also enriched in tumor blood vessels, and have identified a short peptide, 34 amino acids in length, corresponding to the terminal portion of the highly conserved ETS domain that potently blocks the function of ELF-1. A tailored ELF-1 blocking peptide, containing a 12-amino acid HIV-1 TAT protein, readily crosses the cell membrane and enters into the nucleus of endothelial cells, leading to a marked reduction in the expression of ELF-1 gene targets including Tie2 and endothelial nitric oxide synthase. Furthermore, the ELF-1 blocking peptide potently inhibits angiopoietin-1-mediated endothelial cell migration. Systemic administration of this peptide markedly attenuates B16 melanoma tumor growth and tumor-associated angiogenesis in nude mice. These results support the function of ELF-1 in the regulation of Tie2 gene expression during the development of tumor angiogenesis.
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PMID:Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis. 1635 13

Epigenetic mechanisms permit the stable inheritance of cellular properties without changes in DNA sequence or amount. In prostate carcinoma, epigenetic mechanisms are essential for development and progression, complementing, amplifying and diversifying genetic alterations. DNA hypermethylation affects at least 30 individual genes, while repetitive sequences including retrotransposons and selected genes become hypomethylated. Hypermethylation of several genes occurs in a coordinate manner early in carcinogenesis and can be exploited for cancer detection, whereas hypomethylation and further hypermethylation events are associated with progression. DNA methylation alterations interact with changes in chromatin proteins. Prominent alterations at this level include altered patterns of histone modification, increased expression of the EZH2 polycomb histone methyltransferase, and changes in transcriptional corepressors and coactivators. These changes may make prostate carcinoma particularly susceptible to drugs targeting chromatin and DNA modifications. They relate to crucial alterations in a network of transcription factors comprising ETS family proteins, the androgen receptor, NKX3.1, KLF, and HOXB13 homeobox proteins. This network controls differentiation and proliferation of prostate epithelial cells integrating signals from hormones, growth factors and cell adhesion proteins that are likewise distorted in prostate cancer. As a consequence, prostate carcinoma cells appear to be locked into an aberrant state, characterized by continued proliferation of largely differentiated cells. Accordingly, stem cell characteristics of prostate cancer cells appear to be secondarily acquired. The aberrant differentiation state of prostate carcinoma cells also results in distorted mutual interactions between epithelial and stromal cells in the tumor that promote tumor growth, invasion, and metastasis.
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PMID:Epigenetics of prostate cancer: beyond DNA methylation. 1656 24

Testis-specific gene A (TSGA) was originally identified in rat and shown to be expressed within the testes. Here, we have cloned the murine homolog [also known as jumonji domain-containing 1a (Jmjd1a)] and for the first time characterized the TSGA protein and its functions. Although murine TSGA is expressed in testes, its mRNA is also present in many other tissues, including heart, thymus, liver, and skin. Immunostaining revealed that TSGA is a nuclear protein, whose N-terminus contains a putative nuclear localization signal. TSGA displays significant homology to a suspected tumor suppressor and coactivator (5qNCA), to a thyroid hormone receptor interacting protein (TRIP8) and to the corepressor Hairless, pointing at a role of TSGA in transcription regulation. Indeed, TSGA contains several functional transcription repression domains. In addition, TSGA interacts both in vitro and in vivo with ER71 (ETS related 71), a transcription factor that is expressed in the testes of adult mice and during embryogenesis. Specifically, the N-terminus of TSGA and the C-terminus of ER71 are primarily engaged in their complex formation. Furthermore, TSGA impairs the ability of ER71 to activate transcription from the matrix metalloproteinase-1 promoter. Thus, TSGA may modulate the function of ER71 and thereby affect spermatogenesis as well as embryonic development.
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PMID:Repression of transcription by TSGA/Jmjd1a, a novel interaction partner of the ETS protein ER71. 1661 73


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