Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated pancreatic beta-cells.
Biochem J
; 341 ( Pt 2): 315-22, 1999 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-10393088
ABSTRACT
The homeobox gene Pdx-1 plays a key role in the development of the pancreas. In the adult, however, expression of the Pdx-1 gene is restricted to pancreatic beta-cells and endocrine cells of duodenal epithelium. Recently, the transcription factor, upstream stimulatory factor (USF), has been shown to bind in vitro to a mutationally sensitive E-box motif within the 5'-flanking region of the Pdx-1 gene [Sharma, Leonard, Lee, Chapman, Leiter and Montminy (1996) J. Biol. Chem. 271, 2294-2299]. In the present study, we show that USF not only binds to the Pdx-1 gene promoter but also functionally regulates the expression of the Pdx-1 gene in differentiated pancreatic beta-cells. Adenovirus-mediated overexpression of a dominant negative form of USF2 decreased binding of endogenous USF to the E-box element by approximately 90%. This reduction in endogenous USF binding led to a greater than 50% decrease in Pdx-1 gene promoter activity, which, in turn, resulted in marked reductions in Pdx-1 mRNA and protein levels. Importantly, the lower Pdx-1 protein levels led to a greater than 50% reduction in Pdx-1 binding activity to the A3 element on the insulin gene promoter, and a significant reduction in insulin mRNA levels. Overall, our results show that USF functionally regulates Pdx-1 gene expression in differentiated pancreatic beta-cells and provide the first functional data for a role of USF in the regulation of a normal cellular gene.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Transactivadores
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Regulación de la Expresión Génica
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Islotes Pancreáticos
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Proteínas de Homeodominio
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Proteínas de Unión al ADN
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Insulina
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Biochem J
Año:
1999
Tipo del documento:
Article
País de afiliación:
Estados Unidos