Smad2 and 3 mediate transforming growth factor-beta1-induced inhibition of chondrocyte maturation.
Endocrinology
; 141(12): 4728-35, 2000 Dec.
Article
em En
| MEDLINE
| ID: mdl-11108288
ABSTRACT
Transforming growth factor-beta (TGF-beta) is a multifunctional regulator of a variety of cellular functions, including proliferation, differentiation, matrix synthesis, and apoptosis. In growth plate chondrocytes, TGF-beta slows the rate of maturation. Because the current paradigm of TGF-beta signaling involves Smad proteins as downstream regulators of target genes, we have characterized their role as mediators of TGF-beta effects on chondrocyte maturation. Both Smad2 and 3 translocated to the nucleus upon TGF-beta1 signaling, but not upon BMP-2 signaling. Cotransfection experiments using the TGF-beta responsive and Smad3 sensitive p3TP-Lux luciferase reporter demonstrated that wild-type Smad3 potentiated, whereas dominant negative Smad3 inhibited TGF-beta1 induced luciferase activity. To confirm the role of Smad2 and 3 as essential mediators of TGF-beta1 effects on chondrocyte maturation, we overexpressed both wild-type and dominant negative Smad2 and 3 in virally infected chondrocyte cultures. Overexpression of both wild-type Smad2 and 3 potentiated the inhibitory effect of TGF-beta on chondrocyte maturation, as determined by colx and alkaline phosphatase activity, whereas dominant negative Smad2 and 3 blocked these effects. Wild-type and dominant negative forms of Smad3 had more pronounced effects than Smad2. Our results define Smad2 and 3 as key mediators of the inhibitory effect of TGF-beta1 signaling on chondrocyte maturation.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transativadores
/
Fator de Crescimento Transformador beta
/
Condrócitos
/
Proteínas de Ligação a DNA
Limite:
Animals
Idioma:
En
Revista:
Endocrinology
Ano de publicação:
2000
Tipo de documento:
Article
País de afiliação:
Estados Unidos