title: Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model.
abstract: A mouse model that recapitulates the human Ewing's sarcoma-specific chromosomal translocation was generated utilizing the Cre/loxP-mediated recombination technique. A cross between Ewsr1-loxP and Fli1-loxP mice and expression of ubiquitous Cre recombinase induced a specific translocation between Ewsr1 and Fli1 loci in systemic organs of both adult mice and embryos. As a result Ewsr1-Fli1 fusion transcripts were expressed, suggesting a functional Ews-Fli1 protein might be synthesized in vivo. However, by two years of age, none of the Ewsr1-loxP/Fli1-loxP/CAG-Cre (EFCC) mice developed any malignancies, including Ewing-like small round cell sarcoma. Unexpectedly, all the EFCC mice suffered from dilated cardiomyopathy and died of chronic cardiac failure. Genetic recombination between Ewsr1 and Fli1 was confirmed in the myocardial tissue and apoptotic cell death of cardiac myocytes was observed at significantly higher frequency in EFCC mice. Moreover, expression of Ews-Fli1 in the cultured cardiac myocytes induced apoptosis. Collectively, these results indicated that ectopic expression of the Ews-Fli1 oncogene stimulated apoptotic signals, and suggested an important relationship between oncogenic signals and cellular context in the cell-of-origin of Ewing's sarcoma.
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Departments of Pediatrics and Genetics, Washington University School of Medicine, 660 S Euclid Avenue, St. Louis, MO 63110, U.S.A.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.affiliation: Division of Cell Biology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002478:Cells, Cultured; D002875:Chromosomes; D004195:Disease Models, Animal; D018390:Gene Targeting; D056426:Genetic Loci; D008099:Liver / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000737:chemistry / Q000235:genetics*; D034802:RNA-Binding Protein EWS / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015996:Survival Rate; D014178:Translocation, Genetic
chemical_list: C106031:EWS-FLI fusion protein; C497426:Fli1 protein, mouse; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS