Protein kinase A-dependent pSer(675) -ß-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis.
Hepatology
; 58(5): 1713-23, 2013 Nov.
Article
em En
| MEDLINE
| ID: mdl-23744610
ABSTRACT
UNLABELLED Genetically determined loss of fibrocystin function causes congenital hepatic fibrosis (CHF), Caroli disease (CD), and autosomal recessive polycystic kidney disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP). In this study we addressed the relationships between increased cAMP and ß-catenin. In cholangiocytes isolated and cultured from Pkhd1(del4/del4) mice, stimulation of cAMP/PKA signaling (forskolin 10 µM) stimulated Ser(675) -phosphorylation of ß-catenin, its nuclear localization, and its transcriptional activity (western blot and TOP flash assay, respectively) along with a down-regulation of E-cadherin expression (immunocytochemistry and western blot); these changes were inhibited by the PKA blocker, PKI (1 µM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1(del4/del4) cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer(675) -ß-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1(del4/del4) and was inhibited by (1) PKI, (2) silencing ß-catenin (siRNA), and (3) the Rac-1 inhibitor NSC 23766. CONCLUSION:
These data show that in fibrocystin-defective cholangiocytes, cAMP/PKA signaling stimulates pSer(675) -phosphorylation of ß-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer(675) -ß-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1(del4/del4) cholangiocytes. ß-Catenin-dependent changes in cell motility may be central to the pathogenesis of the disease and represent a potential therapeutic target.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas Quinases Dependentes de AMP Cíclico
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Beta Catenina
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Doenças Genéticas Inatas
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Cirrose Hepática
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article