RGD Reference Report - c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration. - Rat Genome Database

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c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration.

Authors: Schwabe, RF  Bradham, CA  Uehara, T  Hatano, E  Bennett, BL  Schoonhoven, R  Brenner, DA 
Citation: Schwabe RF, etal., Hepatology 2003 Apr;37(4):824-32.
RGD ID: 704417
Pubmed: PMID:12668975   (View Abstract at PubMed)
DOI: DOI:10.1053/jhep.2003.50135   (Journal Full-text)

The c-Jun-N-terminal kinase (JNK) pathway is strongly activated after partial hepatectomy (PH), but its role in hepatocyte proliferation is not known. In this study, JNK activity was blocked with the small molecule inhibitor JNK SP600125 in vivo and in vitro as shown by a reduction of c-Jun phosphorylation, AP-1 DNA binding activity, and c-jun messenger RNA (mRNA) expression. SP600125 inhibited proliferating cell nuclear antigen (PCNA) expression, cyclin D1 mRNA and protein expression and reduced mitotic figures after PH. Survival was reduced significantly 3 days after PH in SP600125-treated versus vehicle-treated rats (3 of 11 vs. 8 of 9, P <.01). In epidermal growth factor (EGF)-treated primary cultures of rat hepatocytes, SP600125 decreased (3)H-thymidine uptake, cyclin D1 mRNA and protein expression, and inhibited the EGF-induced transcription of a cyclin D1 promoter-driven reporter gene. The defective regeneration and the decreased survival in SP600125-treated rats did not result from a major increase in apoptosis as shown by normal levels of caspase 3 activity and only slight increases in apoptotic figures. In conclusion, our data show that JNK drives G0 to G1 transition in hepatocytes and that cyclin D1 is a downstream target of the JNK pathway during liver regeneration.

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal liver regeneration  IDA 704417 RGD 
increased cell proliferation  IDA 704417 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Ccnd1  (cyclin D1)

Objects referenced in this article
Gene CCND1 cyclin D1 Homo sapiens

Additional Information