DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy.
PLoS Genet
; 13(3): e1006658, 2017 03.
Article
en En
| MEDLINE
| ID: mdl-28273136
Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of DUX4 in skeletal muscle cells. DUX4 is a transcription factor that activates genes normally associated with stem cell biology and its mis-expression in FSHD cells results in apoptosis. To identify genes and pathways necessary for DUX4-mediated apoptosis, we performed an siRNA screen in an RD rhabdomyosarcoma cell line with an inducible DUX4 transgene. Our screen identified components of the MYC-mediated apoptotic pathway and the double-stranded RNA (dsRNA) innate immune response pathway as mediators of DUX4-induced apoptosis. Further investigation revealed that DUX4 expression led to increased MYC mRNA, accumulation of nuclear dsRNA foci, and activation of the dsRNA response pathway in both RD cells and human myoblasts. Nuclear dsRNA foci were associated with aggregation of the exon junction complex component EIF4A3. The elevation of MYC mRNA, dsRNA accumulation, and EIF4A3 nuclear aggregates in FSHD muscle cells suggest that these processes might contribute to FSHD pathophysiology.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Rabdomiosarcoma
/
ARN Bicatenario
/
Proteínas Proto-Oncogénicas c-myc
/
Apoptosis
/
Proteínas de Homeodominio
/
Distrofia Muscular Facioescapulohumeral
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
PLoS Genet
Asunto de la revista:
GENETICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos