RGD Reference Report - Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease. - Rat Genome Database

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Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease.

Authors: Sato, Y  Harada, K  Kizawa, K  Sanzen, T  Furubo, S  Yasoshima, M  Ozaki, S  Ishibashi, M  Nakanuma, Y 
Citation: Sato Y, etal., Am J Pathol. 2005 Jan;166(1):49-60.
RGD ID: 1582263
Pubmed: PMID:15631999   (View Abstract at PubMed)
PMCID: PMC1602300   (View Article at PubMed Central)
DOI: DOI:10.1016/S0002-9440(10)62231-6   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ERK5 cascade  IMP 1582263 RGD 
positive regulation of epithelial cell proliferation  IDA 1582263 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
apical plasma membrane  IDA 1582263 RGD 
basolateral plasma membrane  IDA 1582263 RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Erk5 MAPK signaling pathway   ISOMap2k5 (Rattus norvegicus)1582263; 1582263 RGD 
Erk5 MAPK signaling pathway   IMP 1582263 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Egfr  (epidermal growth factor receptor)
Map2k5  (mitogen activated protein kinase kinase 5)

Genes (Mus musculus)
Map2k5  (mitogen-activated protein kinase kinase 5)

Genes (Homo sapiens)
MAP2K5  (mitogen-activated protein kinase kinase 5)


Additional Information