RGD Reference Report - Cyclin-dependent kinase 1 plays a critical role in DNA replication control during rat liver regeneration. - Rat Genome Database

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Cyclin-dependent kinase 1 plays a critical role in DNA replication control during rat liver regeneration.

Authors: Garnier, D  Loyer, P  Ribault, C  Guguen-Guillouzo, C  Corlu, A 
Citation: Garnier D, etal., Hepatology. 2009 Dec;50(6):1946-56.
RGD ID: 2316313
Pubmed: PMID:19821535   (View Abstract at PubMed)
DOI: DOI:10.1002/hep.23225   (Journal Full-text)

Liver regeneration is a unique process to restore hepatic homeostasis through rapid and synchronous proliferation of differentiated hepatocytes. Previous studies have shown that hepatocyte proliferation is characterized by high expression levels of the "mitotic" cyclin-dependent kinase 1 (Cdk1) during S-phase compared to other mammalian cells. In the light of findings showing that Cdk1 compensates for the loss of Cdk2 and drives S-phase in Cdk2-deficient cells derived from Cdk2 knockout mice, we took advantage of the models of liver regeneration following partial hepatectomy and primary cultures of normal rat hepatocytes to further examine the involvement of Cdk1 during DNA replication in hepatocytes and to dissect specific cell cycle regulation in hepatocytes compared to control human foreskin fibroblasts. In hepatocytes, Cdk1 exhibited a biphasic activation pattern correlating S-phase and G(2)/M transition, bound to cyclin A or B1 and localized to the nucleus during DNA replication. Importantly, small interfering RNA (siRNA)-mediated silencing of Cdk1 led to a strong decrease in DNA synthesis without affecting centrosome duplication. Furthermore, in hepatocytes arrested by the iron chelator O-Trensox in early S-phase prior to DNA replication, Cdk1/cyclin complexes were active, while replication initiation components such as the minichromosome maintenance 7 (Mcm7) protein were loaded onto DNA. Moreover, Mcm7 expression and loading onto DNA were not modified by Cdk1 silencing. Conversely, in fibroblasts, Cdk1 expression and activation were low in S-phase and its silencing did not reduce DNA synthesis. CONCLUSION: Cdk1 is essential for DNA replication downstream formation of replication initiation complexes in hepatocytes but not in fibroblasts and, as such, our data exemplify crucial differences in the cell cycle regulation between various mammalian cell types.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to epidermal growth factor stimulus  IEP 2316313 RGD 
positive regulation of DNA replication  IMP 2316313 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
histone kinase activity  IDA 2316313histone H1RGD 
protein kinase binding  IPICdk1 (Rattus norvegicus)2316313 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccnb1  (cyclin B1)
Cdk1  (cyclin-dependent kinase 1)
Mcm7  (minichromosome maintenance complex component 7)


Additional Information