The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein.
We have previously shown that cyclin E can malignantly transform primary rat embryo fibroblasts in cooperation with constitutively active Ha-Ras. In addition, we demonstrated that high level cyclin E expression potentiates the development of methyl-nitroso-urea-induced T-cell lymphomas in mice. To further investigate the mechanism underlying cyclin E-mediated malignant transformation, we have performed a mutational analysis of cyclin E function. Here we show that cyclin E mutants defective to form an active kinase complex with Cdk2 are unable to drive cells from G(1) into S phase but can still malignantly transform rat embryo fibroblasts in cooperation with Ha-Ras. In addition, Cdk2 activation is not a prerequisite for the ability of cyclin E to rescue yeast triple cln mutations. We also find that the oncogenic properties of cyclin E did not entirely correspond with its ability to interact with the negative cell cycle regulator p27(Kip1) or the pocket protein p130. These findings suggest that the oncogenic activity of cyclin E does not exclusively rely on its ability as a positive regulator of G(1) progression. Rather, we propose that cyclin E harbors other functions, independent of Cdk2 activation and p27(Kip1) binding, that contribute significantly to its oncogenic activity.
Geisen
Christoph
C
Institut für Zellbiologie (Tumorforschung), IFZ, Universitätsklinikum Essen, Virchowstrasse 173, D-45122 Essen, Germany.
Moroy
Tarik
T
D016475:3T3 Cells; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D051379:Mice; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins; D051381:Rats; D011916:Rats, Inbred F344; D050717:Retinoblastoma-Like Protein p130; D016196:S Phase; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D001798:Blood Proteins; C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019927:Cyclin E; D018076:DNA, Complementary; D011506:Proteins; C493837:RBL2 protein, human; C493838:Rbl2 protein, mouse; C493839:Rbl2 protein, rat; D050717:Retinoblastoma-Like Protein p130; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases