A distant, cis-acting enhancer drives induction of Arf by Tgfß in the developing eye.
Dev Biol
; 380(1): 49-57, 2013 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-23665474
ABSTRACT
The Arf tumor suppressor represents one of several genes encoded at the Cdkn2a and Cdkn2b loci in the mouse. Beyond its role blunting the growth of incipient cancer cells, the Arf gene also plays an essential role in development its gene product, p19(Arf), is induced by Tgfß2 in the developing eye to dampen proliferative signals from Pdgfrß, which effect ultimately fosters the vascular remodeling required for normal vision in the mouse. Mechanisms underlying Arf induction by Tgfß2 are not fully understood. Using the chr4(Δ70 kb/Δ70 kb) mouse, we now show that deletion of the coronary artery disease (CAD) risk interval lying upstream of the Cdkn2a/b locus represses developmentally-timed induction of Arf resulting in eye disease mimicking the persistent hyperplastic primary vitreous (PHPV) found in Arf-null mice and in children. Using mouse embryo fibroblasts, we demonstrate that Arf induction by Tgfß is blocked in cis to the 70 kb deletion, but Arf induction by activated RAS and cell culture "shock" is not. Finally, we show that Arf induction by Tgfß is derailed by preventing RNA polymerase II recruitment following Smad 2/3 binding to the promoter. These findings provide the first evidence that the CAD risk interval, located at a distance from Arf, acts as a cis enhancer of Tgfß2-driven induction of Arf during development.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factor de Crecimiento Transformador beta
/
Elementos de Facilitación Genéticos
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Regulación del Desarrollo de la Expresión Génica
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Factor 1 de Ribosilacion-ADP
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Ojo
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Dev Biol
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos