A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1).
We show here that the adenovirus E1A oncoprotein prevents growth arrest by the CDK2 inhibitor p27(Kip1) (p27) in rodent fibroblasts. However, E1A neither binds p27 nor prevents inhibition of CDK2 complexes in vivo. In contrast, the amount of free p27 available to inhibit cyclin E/CDK2 is increased in E1A-expressing cells, owing to reduced expression of cyclins D1 and D3. Moreover, E1A allows cell proliferation in the presence of supraphysiological p27 levels, while c-Myc, known to induce a cellular p27-inhibitory activity, is only effective against physiological p27 concentrations. E1A also bypasses G1 arrest by roscovitine, a chemical inhibitor of CDK2. Altogether, these findings imply that E1A can act downstream of p27 and CDK2. Retinoblastoma (pRb)-family proteins are known CDK substrates; as expected, association of E1A with these proteins (but not with p300/CBP) is required for E1A to prevent growth arrest by either p27 or the CDK4/6 inhibitor p16(INK4a). Bypassing CDK2 inhibition requires an additional function of E1A: the mutant E1A Delta26-35 does not overcome p27-induced arrest, while it binds pRb-family proteins, prevents p16-induced arrest, and alleviates pRb-mediated repression of E2F-1 transcriptional activity (although E1A Delta26-35 fails to restore expression of E2F-regulated genes in p27-arrested cells). We propose that besides the pRb family, E1A targets specific effector(s) of CDK2 in G1-S control.
Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland.
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Alevizopoulos
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Catarin
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Vlach
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Amati
D016475:3T3 Cells; D017500:Adenovirus E1A Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000818:Animals; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology
D017500:Adenovirus E1A Proteins; C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D006131:Growth Inhibitors; D008869:Microtubule-Associated Proteins; D015513:Oncogene Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D014764:Viral 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