Eukaryotic initiation factor 6 modulates myofibroblast differentiation at transforming growth factor-ß1 transcription level via H2A.Z occupancy and Sp1 recruitment.
J Cell Sci
; 128(21): 3977-89, 2015 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-26395397
ABSTRACT
Eukaryotic initiation factor 6 (eIF6) is a pivotal regulator of ribosomal function, participating in translational control. Previously our data suggested that eIF6 acts as a key binding protein of P311 (a hypertrophic scar-related protein; also known as NREP). However, a comprehensive investigation of its functional role and the underlying mechanisms in modulation of myofibroblast (a key effector of hypertrophic scar formation) differentiation remains unclear. Here, we identified that eIF6 is a novel regulator of transforming growth factor-ß1 (TGF-ß1) expression at transcription level, which plays a key role in myofibroblast differentiation. Mechanistically, this effect is associated with eIF6 altering the occupancy of the TGF-ß1 promoter by H2A.Z (Swiss-Prot P0C0S6) and Sp1. Accordingly, modulation of eIF6 expression in myofibroblasts signiï¬cantly affects their differentiation via the TGF-ß/Smad signaling pathway, which was verified in vivo by the observation that heterozygote eIF6(+/-) mice exhibited enhanced TGF-ß1 production coupled with increased α-smooth muscle actin (α-SMA)(+) myofibroblasts after skin injury. Overall, our data reveal a novel transcriptional regulatory mechanism of eIF6 that acts on facilitating Sp1 recruitment to TGF-ß1 promoter via H2A.Z depletion and thus results in increased TGF-ß1 transcription, which contributes to myofibroblast differentiation.
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Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
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Fatores de Iniciação de Peptídeos
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Fator de Transcrição Sp1
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Fator de Crescimento Transformador beta1
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Miofibroblastos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article