Document Detail


EWS/ATF1 expression induces sarcomas from neural crest-derived cells in mice.
MedLine Citation:
PMID:  23281395     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest-derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.
Authors:
Kazunari Yamada; Takatoshi Ohno; Hitomi Aoki; Katsunori Semi; Akira Watanabe; Hiroshi Moritake; Shunichi Shiozawa; Takahiro Kunisada; Yukiko Kobayashi; Junya Toguchida; Katsuji Shimizu; Akira Hara; Yasuhiro Yamada
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-02
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  600-10     Citation Subset:  AIM; IM    
Affiliation:
Department of Orthopedic Surgery, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE41123
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MeSH Terms
Descriptor/Qualifier:
Activating Transcription Factor 1 / genetics*
Animals
Base Sequence
Cell Line, Tumor
Cell Lineage / genetics
Cell Proliferation
Gene Expression
Gene Fusion
Genes, fos
Humans
Mice
Mice, Transgenic
Neural Crest / pathology
Oncogene Proteins, Fusion / genetics
RNA, Small Interfering / genetics
RNA-Binding Protein EWS / genetics*
Sarcoma, Clear Cell / etiology,  genetics*,  pathology
Transcription Factors / genetics
Chemical
Reg. No./Substance:
0/Activating Transcription Factor 1; 0/Atf1 protein, mouse; 0/EWS-ATF1 fusion protein, human; 0/Oncogene Proteins, Fusion; 0/RNA, Small Interfering; 0/RNA-Binding Protein EWS; 0/Transcription Factors
Comments/Corrections

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