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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aberrant transcription factors associated with many human malignancies function by deregulation of tumorigenic pathways. However, identification of these pathways has come slowly. Virtually all cases of Ewing's Sarcoma and peripheral Primitive Neuroectodermal Tumor (PNET) are associated with aberrant transcription factors which fuse amino-terminal EWS with the DNA binding moiety of an ETS transcription factor (FLI-1 in 90% of cases). Attempts to identify the downstream targets of these chimeras in the Ewing Family Tumors (EFT) on the basis of differential gene regulation have produced little association with tumor biology. As an alternative approach, we have used highly efficient retroviral systems to biologically screen cDNA derived from cells transformed by EWS/FLI-1. We have identified the recently described PDGF-C as target of EWS/ETS transcriptional deregulation. This transcriptional deregulation is specific to EWS/FLI. PDGF-C possesses substantial biologic activity in vitro and in vivo. It is expressed in EFT cell lines and in primary tumors. Within these EFT cell lines, PDGF-C expression is dependent upon EWS/FLI activity. These results suggest that PDGF-C may be a significant mediator of EWS/FLI driven oncogenesis.
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PMID:PDGF-C is an EWS/FLI induced transforming growth factor in Ewing family tumors. 1131 95

The functional characterization of ETS transcription factors have allowed the association of numerous physiological and pathological roles to these proteins in the regulation of gene expression during the maturation of hematopoietic cell lineages and in tumor cell growth, invasion, and metastasis. Moreover, structural investigations have allowed the determination of certain amino acid domains of ETS proteins that are essential for the recognition and transcriptional activation or repression of gene promoters or enhancers. It has been observed that the mechanisms of action of ETS proteins can be ruled in part by their intermolecular interactions with other transcription factors and by their phosphorylation status. This review describes information about structure-function relationships of different ETS family members in order to establish the structural differences that are important for their affinities and intrinsic activities to DNA binding sites.
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PMID:Structure-function studies of ETS transcription factors. 1135 68

TEL (Translocation-ETS-Leukemia or ETV 6) is disrupted by multiple chromosomal translocations in acute leukemia. The loss of heterozygosity at the TEL locus in leukemias and the hemizygous deletion of TEL that is observed in various tumors, suggests that TEL is a tumor suppressor. Overexpression of TEL alters cellular morphology and represses the expression of the matrix metalloproteinase stromelysin-1. Based on these studies, deletion analysis was used to define the minimal repression domains of TEL. TEL-mediated repression required both the N-terminal pointed domain and a central region composed of amino acids 268-303. The mSin3A and N-CoR corepressors bind to the pointed domain and the central repression domain of TEL, respectively. Unexpectedly, histone deacetylase-3, but not other histone deacetylases, also associates with the central region of TEL. Histone deacetylase-3 interacts with a TEL mutant that cannot bind N-CoR, suggesting that this is a direct interaction with TEL. In addition, histone H3 was under-acetylated near the TEL-binding sites in the endogenous stromelysin-1 promoter when TEL was expressed. Furthermore, trichostatin A, a potent histone deacetylase inhibitor, impaired TEL-dependent repression of the stromelysin-1 promoter. Finally, while TEL-expression induced cellular aggregation of Ras-transformed cells, Trichostatin A reversed the TEL-induced cellular aggregation phenotype. Thus, the cumulative data suggests that histone deacetylase-3 activity is required for the transcriptional functions of TEL.
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PMID:TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. 1143 34

The Ewing tumor family includes classical Ewing's sarcoma of bone and soft tissues, peripheral primitive neuroectodermal tumors (pPNET), Askin tumor, and other less frequent variants. This group of tumors is defined by the consistent presence of chromosomal translocations resulting in gene fusions between EWS gene and a member of the ETS family of transcription factors, mainly FLI1 and ERG. Analogous fusions are seen in other solid developmental tumors, like desmoplastic small round cell tumor. These fusions, which are consistently present and tumor-specific, control transcription of several target genes, largely unknown but critical to cell proliferation and differentiation. Therefore, gene fusions are useful to diagnose and classify small round cell tumors, have prognostic significance, are probably useful to detect micrometastasis and monitor minimal residual disease, and are potential therapeutic targets. Secondary molecular alterations, which include mutations of cell cycle regulatory genes, are not tumor-specific but are related to progression and may have prognostic value. The Ewing tumor family represents a paradigm of the application of the knowledge of biology of neoplasia to the clinical management of patients.
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PMID:Ewing tumor: tumor biology and clinical applications. 1146 51

Fli-1 protein, a member of the ETS family of DNAbinding transcription factors, is involved in cellular proliferation and tumorigenesis. Approximately 90% of Ewing's sarcoma/primitive neuroectodermal tumors (ES/PNET) have a specific translocation, t(11;22)(q24;q12), which results in fusion of EWS to Fli-1, and production of an EWS-Fli-1 fusion protein. We have recently shown that immunohistochemistry for the carboxy terminal of Fli-1 protein is sensitive and highly specific for the diagnosis of ES/PNET. In our earlier study we noted that among normal tissues only endothelial cells and small lymphocytes expressed Fli-1. Fli-1 expression in vascular neoplasms has not been previously studied. Formalin-fixed paraffin-embedded tissue from 54 vascular tumors and 75 nonvascular tumors were immunostained for Fli-1 (1:120, Sc 356, Santa Cruz Biotechnology, Santa Cruz, CA), after steam heat-induced epitope retrieval. Only cases with >10% of cells showing nuclear staining were accepted as positive. Cases without positive internal controls (endothelium and small lymphocytes) were not scored. Positive internal controls were present in 122 of 129 cases (95%). One vascular tumor (Kaposi's sarcoma) and 7 nonvascular tumors (2 epithelioid sarcomas and 5 carcinomas) without internal controls were not scored. Fli-1 was expressed by 50 of 53 vascular tumors scored (94%), including 20 of 22 angiosarcomas, 11 of 12 hemangioendotheliomas, 7 of 7 hemangiomas, and 12 of 12 Kaposi's sarcomas. In contrast, Fli-1 expression was absent in the 68 nonvascular tumors scored (0 of 68), including 16 sarcomas, 7 melanomas, and 45 carcinomas. The results of this study strongly suggest a role for Fli-1 as a novel marker of both benign and malignant vascular tumors. The sensitivity (94%) and specificity (100%) of Fli-1 with regards to the cases evaluated in this study equal or exceed those of the established vascular markers, CD31, CD34, and von Willebrand factor. As the first nuclear, rather than cytoplasmic or membranous marker of endothelium, Fli-1 immunostaining also generally lacks cytoplasmic staining artifacts that are the result of endogenous peroxidases or biotin.
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PMID:Expression of Fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. 1147 91

EWS encodes a ubiquitously expressed RNA binding protein with largely unknown function. In Ewing sarcoma family tumors (EFT), one allele is rearranged with an ETS gene. This is the first description of an EFT with a complete EWS deficiency in the presence of two copies of a rearranged chromosome 22 carrying an interstitial EWS-FLI1 translocation. Absence of EWS protein suggested that it is dispensable for EFT growth. By sequencing of EWS cDNA from unrelated EFTs, we excluded inactivation of EWS as a general mechanism in EFT pathogenesis. Rather, EWS was found to be uniformly expressed in two splicing variants of similar abundancy, EWSalpha and EWSbeta, which differ in a single amino acid. Three EWS negative cell lines were established, which will serve as valuable models to study normal and aberrant EWS function upon reintroduction into the tumor cells.
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PMID:The EWS protein is dispensable for Ewing tumor growth. 1150 40

Ewing tumors are characterized by reciprocal translocations involving the EWS gene on 22q12 fused to ETS transcription-factor family members. Little is known about further aberrations contributing to tumor development and progression. Sixty-two frozen tumors with known EWS rearrangements (52 primary tumors, 10 relapses) of ET patients registered in the EICESS protocol were analyzed by comparative genomic hybridization (CGH). The median number of changes in 52 primary and 10 relapsed cases was 2.5 and 5.0 per tumor (P = 0.153). Frequent abnormalities included gains of chromosomes 8, 12, 20, and 1q and losses of 16q and 19q. Neither number nor type of aberration was associated with histology, tumor size, disease stage, tumor localization, or histologic tumor response to chemotherapy. Among the 52 primary tumors, 26 with Type I fusion (EWS exon 7 to FLI1 exon 6) and 26 with other fusion types had a median of 2.0 and 3.0 aberrations per tumor, respectively (P = 0.031). Combinations of gains of chromosomes 8 and 12, gains of chromosome 20, and either gains of 8q or 18q and losses of 16q and 17p frequently occurred. The cumulative overall survival (OAS) was different between 35 patients with <5 aberrations and 13 patients with > or =5 aberrations (P = 0.009). Univariate analysis showed that patients with gains of 1q, 2q, 12, and 20 or losses of 16q and 17p had significantly lower OAS than those without aberrations. By multivariate analysis, loss of 16q (relative risk [RR] = 5.3; P = 0.0006) was an independent prognostic factor.
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PMID:Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. 1155 Feb 84

Specific chromosomal translocations involving the ews gene and one of five members of the ets family of transcription factors create ews/ets fusion genes that are found in approximately 85% of Ewing's family of tumors. ews/ets fusion genes consistently maintain an intact and functional ets DNA binding domain (DBD) in all of these cases. We demonstrate here, however, that EWS/FLI1, the most prevalent EWS/ETS fusion, activates oncogenic pathways independent of its DBD. In in vivo tumor assays, EWS/FLI1 molecules with either point mutations or a large deletion in the ets DBD retain the ability to accelerate tumors in NIH 3T3 cells, whereas they lose the ability to bind DNA in vitro. Additionally, whereas inhibition of DBD functions of EWS/FLI1 with a dominant negative form of FLI1 is sufficient to inhibit anchorage-independent growth in NIH 3T3 cells, it is ineffective in inhibiting tumor growth in SCID mice. Usage of this dominant negative construct in a Ewing's tumor cell line, however, does reduce the rate of tumor formation, supporting the need for a functional DBD in this context. Together, these results suggest that EWS/FLI1 induces both DBD-dependent and DBD-independent oncogenic pathways.
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PMID:DNA binding domain-independent pathways are involved in EWS/FLI1-mediated oncogenesis. 1155 28

In this study, we show that the ETS transcription factor ER81 directly binds to and activates the promoter of the matrix metalloproteinase gene, MMP-1. Further, the oncoprotein HER2/Neu synergizes with ER81 to stimulate MMP-1 transcription. The activation of ER81 by HER2/Neu is mediated by MAP kinases, which phosphorylate ER81 in its N-terminal activation domain. Four respective phosphorylation sites have been identified. Blocking phosphorylation at these sites decreases ER81 transcriptional activity, which can be further diminished by abolishment of phosphorylation at two non-MAP kinase sites. Altogether, our results reveal mechanisms of how phosphorylation of ER81 regulates the expression of target genes such as MMP-1, which may be important for many physiological processes from embryogenesis to adulthood as well as for tumor metastasis.
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PMID:HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1. 1159 30

Tumor-associated chromosomal translocations lead to the formation of chimeric fusions between the EWS gene and one of five different ETS transcription factors in Ewing's family tumors (EFTs). The resultant EWS/ETS proteins promote oncogenesis in a dominant fashion in model systems and are necessary for continued growth of EFT cell lines. EWS belongs to a family of genes that encode proteins that may serve as adapters between the RNA polymerase II complex and RNA splicing factors. EWS/ETS fusions have biochemical characteristics of aberrant transcription factors and appear to promote abnormal cellular growth by transcriptionally modulating a network of target genes. Early evidence suggests that EWS/ETS proteins may also impact gene expression through alteration in RNA processing. Elucidation of EWS/ETS target gene networks in the context of other signaling pathways will hopefully lead to biology based therapeutic strategies for EFT.
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PMID:Biology of EWS/ETS fusions in Ewing's family tumors. 1160 24


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