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Query: UNIPROT:P06889 (Mol)
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Human chromosome 21 is the smallest human autosome and many important genetic/familial disorders map to this chromosome, e.g., familial amyotrophic lateral sclerosis (FALS), Down syndrome, Alzheimer's disease and some cases of Ewings sarcoma. Hence, the identification of genes localised to this chromosome and studies on their normal biological function and their role in disease is gaining momentum. The use of animal models to generate gain- and loss-of-function mutations is an important element of these studies on functionality/pathology and has yielded powerful insights. However, no animal model has yet been generated that exactly models any of the disorders associated with this chromosome. The major utility of the animal models has been to illuminate the biological functions of genes and the causation of pathophysiology of diseases associated with genes on this chromosome.
Hum Mol Genet 1997
PMID:Animal models in the study of the biological function of genes on human chromosome 21 and their role in the pathophysiology of Down syndrome. 930 Jun 64

The t(11;22) chromosomal translocation specifically linked to Ewing sarcoma and primitive neuroectodermal tumor results in a chimeric molecule fusing the amino-terminus-encoding region of the EWS gene to the carboxyl-terminal DNA-binding domain encoded by the FLI-1 gene. As the function of the protein encoded by the EWS gene remains unknown, we investigated the putative role of EWS in RNA polymerase II (Pol II) transcription by comparing its activity with that of its structural homolog, hTAFII68. We demonstrate that a portion of EWS is able to associate with the basal transcription factor TFIID, which is composed of the TATA-binding protein (TBP) and TBP-associated factors (TAFIIs). In vitro binding studies revealed that both EWS and hTAFII68 interact with the same TFIID subunits, suggesting that the presence of EWS and that of hTAFII68 in the same TFIID complex may be mutually exclusive. Moreover, EWS is not exclusively associated with TFIID but, similarly to hTAFII68, is also associated with the Pol II complex. The subunits of Pol II that interact with EWS and hTAFII68 have been identified, confirming the association with the polymerase. In contrast to EWS, the tumorigenic EWS-FLI-1 fusion protein is not associated with either TFIID or Pol II in Ewing cell nuclear extracts. These observations suggest that EWS and EWS-FLI-1 may play different roles in Pol II transcription.
Mol Cell Biol 1998 Mar
PMID:EWS, but not EWS-FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes. 948 65

We report two cases of desmoplastic small round cell tumor (DSRCT) with novel molecular variants of the specific EWS-WT1 gene fusion. This fusion usually encodes a chimeric RNA with an in-frame junction of exon 7 of EWS to exon 8 of WT1. In one variant patient, the EWS-WT1 fusion transcript contained an in-frame junction of exon 9 of EWS to exon 8 of WT1. Moreover, in this patient the tumor arose in the hand, an extremely unusual site for DSRCT. In the second patient, an in-frame junction of exon 10 of EWS to exon 8 of WT1 was present. These two cases of DSRCT show that the molecular variability in the EWS breakpoint observed in the EWS-FLI1 fusion of Ewing's sarcoma can occur in DSRCT as well. This type of heterogeneity is relevant to the interpretation of molecular diagnostic assays and could also affect the functional properties of the encoded chimeric transcription factors.
Diagn Mol Pathol 1998 Feb
PMID:Molecular variants of the EWS-WT1 gene fusion in desmoplastic small round cell tumor. 964 31

FAK is a nonreceptor tyrosine kinase involved in adhesion-mediated signal transduction whose level of expression is related to the invasiveness of malignant tumors. In seeking strategies to downregulate FAK, we treated various cell lines in vitro with the benzoquinone ansamycin geldanamycin (GA) which was previously described as a tyrosine kinase inhibitor, but recently has been shown to exert its effects by interfering with the chaperone function of members of the hsp90 family of heat-shock proteins. We evaluated the effects of benzoquinone ansamycins on FAK steady-state protein level and FAK half-life in breast and prostate carcinoma, Ewing's sarcoma, and 3T3 fibroblasts. Our data demonstrate that GA stimulates the proteolytic degradation of FAK in all cell lines examined and markedly reduces the half-life of newly synthesized FAK protein without significantly altering the level of FAK mRNA. These data demonstrate FAK to be another tyrosine kinase sensitive to the destabilizing effects of benzoquinone ansamycins and further show that small molecule-mediated pharmacologic modulation of FAK protein level is a feasible approach to the interdiction of FAK function.
Mol Genet Metab 1999 Jan
PMID:The benzoquinone ansamycin geldanamycin stimulates proteolytic degradation of focal adhesion kinase. 997 44

Background: Soft tissue tumors often present a major diagnostic challenge for the pathologist. The correct diagnosis has important prognostic and therapeutic consequences. In recent years significant progress has been made in identifying characteristic chromosomal abnormalities associated with certain solid tumors. More than 85% of tumors in the Ewing's sarcoma (ES) family contain a specific t(11;22) (q24;q12) translocation. Methods and Results: We present six patients with a soft tissue tumor of which only four were diagnosed primarily as belonging to the ES family. All cases were further examined by the following methods: immunohistochemistry with MIC2, cytogenetics, nested reverse transcription-polymerase chain reaction of the t(11;22), using fresh-frozen or formalin-fixed, paraffin-embedded archival material. Conclusions: This method clearly allowed the diagnosis of a tumor of the ES family in all six cases.
Mol Diagn 1997 Mar
PMID:Modern Diagnostic Methods in Ewing's Sarcoma Family: Six Patients With Histologic Soft Tissue Tumors. 1046 87

The FUS (TLS)-ERG chimeric protein associated with t(16;21)(p11;q22) acute myeloid leukemia is structurally similar to the Ewing's sarcoma chimeric transcription factor EWS-ERG. We found that both FUS-ERG and EWS-ERG could induce anchorage-independent proliferation of the mouse fibroblast cell line NIH 3T3. However, only FUS-ERG was able to inhibit the differentiation into neutrophils of a mouse myeloid precursor cell line L-G and induce its granulocyte colony-stimulating factor-dependent growth. We constructed several deletion mutants of FUS-ERG lacking a part of the N-terminal FUS region. A deletion mutant lacking the region between amino acids 1 and 173 (exons 1 to 5) lost the NIH 3T3-transforming activity but retained the L-G-transforming activity. On the other hand, a mutant lacking the region between amino acids 174 and 265 (exons 6 and 7) lost the L-G-transforming activity but retained the NIH 3T3-transforming activity. These results indicate that the N-terminal region of FUS contains two independent functional domains required for the NIH 3T3 and L-G transformation, which we named TR1 and TR2, respectively. Although EWS intrinsically possessed the TR2 domain, the EWS-ERG construct employed lacked the EWS sequence containing this domain. Since the TR2 domain is always found in chimeric proteins identified from t(16;21) leukemia patients but not in chimeric proteins from Ewing's sarcoma patients, it seems that the TR2 function is required only for the leukemogenic potential. In addition, we identified three cellular genes whose expression was altered by ectopic expression of FUS-ERG and found that these are regulated in either a TR1-dependent or a TR2-dependent manner. These results suggest that FUS-ERG may activate two independent oncogenic pathways during the leukemogenic process by modulating the expression of two different groups of genes simultaneously.
Mol Cell Biol 1999 Nov
PMID:Dual transforming activities of the FUS (TLS)-ERG leukemia fusion protein conferred by two N-terminal domains of FUS (TLS). 1052 52

The ETS family member Tel is rearranged in human leukemia of both myeloid and lymphoid origin while the ETS member Fli-1 is insertionally activated in Friend erythroleukemia in mice and is translocated to the EWS locus in Ewing's sarcoma. In previous studies we demonstrated that Tel binds to Fli-1 and blocks transactivation of megakaryocytic promoters by Fli-1. In this study we demonstrate that expression of Fli-1 in the leukemia cell line K562 induces a megakaryocytic phenotype and the expression of the platelet markers GPIX, GP1balpha, and GPIIb. Introduction of Tel blocked the megakaryocytic phenotype induced by Fli-1, suggesting a biological correlation to the biochemical interaction of Tel and Fli-1 reported previously.
Blood Cells Mol Dis 2000 Feb
PMID:The ETS family member Tel antagonizes the Fli-1 phenotype in hematopoietic cells. 1077 79

CD31 has been shown to be a sensitive and specific marker for endothelial differentiation among epithelioid and spindled-pleomorphic human neoplasms. However, the role of this marker in the evaluation of small round cell tumors has not been evaluated. Formalin-fixed, paraffin-embedded tissue sections from 276 small round cell tumors, including 85 Ewing's sarcoma/primitive neuroectodermal tumors (ES/PNET), 52 rhabdomyosarcomas, 10 extraabdominal polyphenotypic small cell tumors, six desmoplastic small cell tumors, 11 neuroblastomas, 23 Wilms' tumors, 20 retinoblastomas, 13 esthesioneuroblastomas, and 56 small cell malignant lymphomas were stained with CD31 (JC/70A, 1:40), using a modified avidinbiotin-peroxidase complex technique, after citrate buffer microwave epitope retrieval. Among nonlymphoid small round cell tumors, four of 85 ES/PNET were at least focally reactive. No other lesion in this group was positive. In contrast, the majority of well-differentiated (11 of 17), intermediately differentiated (two of three), and lymphoblastic lymphomas (three of three) were positive. Small cleaved lymphomas (three of 13 follicular, one of 13 diffuse) were less often reactive, whereas small noncleaved lesions were negative. Although reactivity for CD31 in ES/PNET is uncommon, the presence of platelet/endothelial cell adhesion molecule in a small cell neoplasm should not in isolation be taken as evidence of hematopoietic origin. These results further define the utility of CD31 in the evaluation of human neoplasms.
Appl Immunohistochem Mol Morphol 2000 Mar
PMID:CD31 immunoreactivity in small round cell tumors. 1112 27

This study describes a new case of Ewing sarcoma (ES)-peripheral primitive neuroectodermal tumor (pPNET) with unusual phenotype and fusion gene structure. The tumor located in the inguinal area of a 15-year-old boy showed a highly aggressive behavior with hematogenous metastases after intensive chemotherapy and bone marrow transplant, causing death 28 months after diagnosis. The tumor displayed a clear cell pattern, and several neuroectodermal markers proved positive both in the original tumor and in xenografts. This neuroectodermal character was confirmed by electron microscopy. Moreover, cytogenetically the tumor has an unusual chromosomal rearrangement, t(2;22)(q13;q22,t(3;18)(p21;q23); representing a new EWS-FEV fusion type in which exon 7 of EWS gene is fused with exon 2 of FEV gene. This is the third published study of an ES-pPNET showing EWS-FEV fusion described, but it is the first study of a tumor with the aforementioned fusion points. These findings support the genetic and morphologic heterogeneity existing within the group of ES-pPNET tumors.
Diagn Mol Pathol 2000 Sep
PMID:Soft tissue Ewing sarcoma--peripheral primitive neuroectodermal tumor with atypical clear cell pattern shows a new type of EWS-FEV fusion transcript. 1097 20

Genetic alterations occurring in various chromosomes have been described in many human tumors. The DCC gene was originally identified in colorectal cancer and was reported as a tumor suppressor gene that might be related to tumor metastasis. We investigated 10 cell lines and 15 fresh tumors of childhood rhabdomyosarcoma, 7 cell lines of Ewing's sarcoma, and 4 cell lines of primitive neuroectodermal tumor (PNET) for the expression and mutation of DCC gene by RT-PCR analysis and PCR-single stranded conformation polymorphism (SSCP) analysis. Twenty-five pairs of primers were used for PCR-SSCP. Six of ten (60%) cell lines of rhabdomyosarcoma and 3 of 7 (43%) cell lines of Ewing's sarcoma showed reduced or absent expression of DCC gene. There was no mobility shift within 24 exons by SSCP analysis, although 3 types of polymorphism were found at codon 201 in exon 3. Direct sequencing of different bands showed types I, II, and I/II representative of codon 201Gly, codon 201Arg, and codon 201Gly/Arg, respectively. The proportion of type I between fresh rhabdomyosarcoma and normal controls was not significant. Our results suggested that the inactivation of DCC gene may play a role in the pathogenesis of a subset of rhabdomyosarcoma and Ewing's sarcoma.
Int J Mol Med 2000 Oct
PMID:Reduced or absent expression and codon 201Gly/Arg polymorphism of DCC gene in rhabdomyosarcoma and Ewing's sarcoma/PNET family. 1099 40


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