RGD Reference Report - CDK2 regulation through PI3K and CDK4 is necessary for cell cycle progression of primary rat hepatocytes. - Rat Genome Database

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CDK2 regulation through PI3K and CDK4 is necessary for cell cycle progression of primary rat hepatocytes.

Authors: Wierod, L  Rosseland, CM  Lindeman, B  Oksvold, MP  Grosvik, H  Skarpen, E  Huitfeldt, HS 
Citation: Wierod L, etal., Cell Prolif. 2007 Aug;40(4):475-87.
RGD ID: 1642396
Pubmed: PMID:17635516   (View Abstract at PubMed)
PMCID: PMC6495152   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1365-2184.2007.00451.x   (Journal Full-text)

INTRODUCTION/OBJECTIVES: Cell cycle progression is driven by the coordinated regulation of cyclin-dependent kinases (CDKs). In response to mitogenic stimuli, CDK4 and CDK2 form complexes with cyclins D and E, respectively, and translocate to the nucleus in the late G(1) phase. It is an on-going discussion whether mammalian cells need both CDK4 and CDK2 kinase activities for induction of S phase. METHODS AND RESULTS: In this study, we have explored the role of CDK4 activity during G(1) progression of primary rat hepatocytes. We found that CDK4 activity was restricted by either inhibiting growth factor induced cyclin D1-induction with the PI3K inhibitor LY294002, or by transient transfection with a dominant negative CDK4 mutant. In both cases, we observed reduced CDK2 nuclear translocation and reduced CDK2-Thr160 phosphorylation. Furthermore, reduced pRb hyperphosphorylation and reduced cellular proliferation were observed. Ectopic expression of cyclin D1 alone was not sufficient to induce CDK4 nuclear translocation, CDK2 activity or cell proliferation. CONCLUSIONS: Thus, epidermal growth factor-induced CDK4 activity was necessary for CDK2 activation and for hepatocyte proliferation. These results also suggest that, in addition to regulating cyclin D1 expression, PI3K is involved in regulation of nuclear shuttling of cyclin-CDK complexes in G(1) phase.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of cell population proliferation  IMP 1642396 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cdk4  (cyclin-dependent kinase 4)

Objects referenced in this article
Gene Pik3cg phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma Rattus norvegicus

Additional Information