| [PMID]: | 22570737 |
| [Au] Autor: | Suzuki K; Matsui Y; Higashimoto M; Kawaguchi Y; Seki S; Motomura H; Hori T; Yahara Y; Kanamori M; Kimura T |
| [Ad] Dirección: | Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Japan. |
| [Ti] Título: | Myxoid liposarcoma-associated EWSR1-DDIT3 selectively represses osteoblastic and chondrocytic transcription in multipotent mesenchymal cells. |
| [So] Fuente: | PLoS One;7(5):e36682, 2012. |
| [Is] ISSN: | 1932-6203 |
| [Cp] País de publicación: | United States |
| [La] Idioma: | eng |
| [Ab] Resumen: | BACKGROUND: Liposarcomas are the most common class of soft tissue sarcomas, and myxoid liposarcoma is the second most common liposarcoma. EWSR1-DDIT3 is a chimeric fusion protein generated by the myxoid liposarcoma-specific chromosomal translocation t(12;22)(q13;q12). Current studies indicate that multipotent mesenchymal cells are the origin of sarcomas. The mechanism whereby EWSR1-DDIT3 contributes to the phenotypic selection of target cells during oncogenic transformation remains to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Reporter assays showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells. Specifically, the osteoblastic marker Opn promoter and chondrocytic marker Col11a2 promoter were repressed, while the adipocytic marker Ppar-γ2 promoter was not affected. Mutation analyses, transient ChIP assays, and treatment of cells with trichostatin A (a potent inhibitor of histone deacetylases) or 5-Aza-2'-deoxycytidine (a methylation-resistant cytosine homolog) revealed the possible molecular mechanisms underlying the above-mentioned selective transcriptional repression. The first is a genetic action of the EWSR1-DDIT3 fusion protein, which results in binding to the functional C/EBP site within Opn and Col11a2 promoters through interaction of its DNA-binding domain and subsequent interference with endogenous C/EBPß function. Another possible mechanism is an epigenetic action of EWSR1-DDIT3, which enhances histone deacetylation, DNA methylation, and histone H3K9 trimethylation at the transcriptional repression site. We hypothesize that EWSR1-DDIT3-mediated transcriptional regulation may modulate the target cell lineage through target gene-specific genetic and epigenetic conversions. CONCLUSIONS/SIGNIFICANCE: This study elucidates the molecular mechanisms underlying EWSR1-DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development. A better understanding of this process is fundamental to the elucidation of possible direct lineage reprogramming in oncogenic sarcoma transformation mediated by fusion proteins. |
| [Mh] Términos MeSH primario: |
Liposarcoma Mixoide/genética
Liposarcoma Mixoide/metabolismo
Células del Estroma Mesenquimatoso/metabolismo
Células Madre Multipotentes/metabolismo
Proteínas de Fusión Oncogénica/metabolismo
Proteínas Represoras/metabolismo
Transcripción Genética
|
| [Mh] Términos MeSH secundario: |
Animales
Secuencia de Bases
Sitios de Unión
Proteínas Potenciadoras de Unión a CCAAT/química
Proteínas Potenciadoras de Unión a CCAAT/metabolismo
Proteínas de Unión a Calmodulina/metabolismo
Línea Celular
Condrocitos/metabolismo
Colágeno Tipo XI/genética
Metilación de ADN
Histona Desacetilasas/metabolismo
Humanos
Leucina Zippers
Ratones
Modelos Biológicos
Datos de Secuencia Molecular
Proteínas de Fusión Oncogénica/química
Proteínas de Fusión Oncogénica/genética
Osteoblastos/metabolismo
Osteopontina/genética
PPAR gamma/genética
Regiones Promotoras Genéticas
Unión Proteica
ARN Mensajero/metabolismo
Proteínas de Unión al ARN/metabolismo
Factor de Transcripción CHOP/metabolismo
Activación Transcripcional
Translocación Genética
|
| [Pt] Tipo de publicación: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nombre de substancia:
| 0 (CCAAT-Enhancer-Binding Proteins); 0 (Calmodulin-Binding Proteins); 0 (Col11a2 protein, mouse); 0 (Collagen Type XI); 0 (EWSR1 protein, human); 0 (EWSR1-DDIT3 protein, human); 0 (Oncogene Proteins, Fusion); 0 (PPAR gamma); 0 (RNA, Messenger); 0 (RNA-Binding Proteins); 0 (Repressor Proteins); 106441-73-0 (Osteopontin); 147336-12-7 (Transcription Factor CHOP); EC 3.5.1.98 (Histone Deacetylases) |
| [Em] Mes de ingreso: | 1301 |
| [Cu] Fecha actualización por clase: | 130520 |
| [Lr] Fecha última revisión: | 130520 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Fecha de ingreso para procesamiento: | 120509 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1371/journal.pone.0036682 |
