Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease
| Autor: | Takahiro Sanzen, Yasuni Nakanuma, Kenichi Harada, Mitsue Yasoshima, Kazuo Kizawa, Masahiko Ishibashi, Shinichi Furubo, Yasunori Sato, Satoru Ozaki |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty Caroli disease Biology MAP Kinase Kinase 5 Polymerase Chain Reaction Pathology and Forensic Medicine Epidermal growth factor Internal medicine medicine Polycystic kidney disease Animals RNA Messenger Protein kinase A Cells Cultured Mitogen-Activated Protein Kinase 7 DNA Primers Oligonucleotide Array Sequence Analysis Polycystic Kidney Diseases Epidermal Growth Factor Kinase Hepatobiliary disease Rats Inbred Strains medicine.disease Caroli Disease Rats ErbB Receptors Original Research Paper Disease Models Animal Endocrinology Bile Ducts Intrahepatic Mitogen-activated protein kinase Cancer research biology.protein Cell Division |
| Zdroj: | The American journal of pathology. 166(1) |
| ISSN: | 0002-9440 |
| Popis: | Polycystic kidney (PCK) rats exhibit a multiorgan cyst pathology similar to human autosomal recessive polycystic kidney disease, and are proposed as an animal model of Caroli’s disease with congenital hepatic fibrosis (CHF). This study investigated the expression and function of selected components of the mitogen activated protein kinase (MAPK) pathway in cultured intrahepatic biliary epithelial cells (BECs) of PCK rats. Compared to the proliferative activity of cultured BECs of control rats, those of the PCK rats were hyperresponsive to epidermal growth factor (EGF). The increase in BEC proliferation was accompanied by overexpression of MAPK/extracellular signal-regulated protein kinase (ERK) kinase 5 (MEK5), and subsequent phosphorylation of ERK5 in vitro. The increased proliferative activity was significantly inhibited by the transfection of short interfering RNA against MEK5 mRNA. An EGF receptor tyrosine kinase inhibitor, gefitinib (“Iressa”, ZD1839), also significantly inhibited the abnormal growth of cultured BECs of PCK rats. By contrast, treatment with PD98059 and U0126, inhibitors for MEK1/2, was less effective. These results suggest that the activation of the MEK5-ERK5 cascade plays a pivotal role in the biliary dysgenesis of PCK rats, and also provide insights into the pathogenesis of Caroli’s disease with CHF. As the MEK5-ERK5 interaction is highly specific, it may represent a potential target of therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|