Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit.
The cyclin-dependent kinases cdk2 and cdk3 are required for the G1-S transition in mammalian cells. Here we show that G1 arrest induced by the corresponding dominant-negative mutants of these enzymes, cdk2dn or cdk3dn, is resistant to the action of SV40 T antigen (T). In the presence of cdk2dn, T released ... active E2F from negative control by pRb and its related family members (pocket proteins) but failed to induce S-phase. Therefore, among other targets, cdk2 also phosphorylates nonpocket protein substrates in promoting S-phase entry, and T does not mimic all cdk2 functions. In the presence of cdk3dn, however, T failed to induce cell cycle progression or stimulate E2F-dependent transcription activity. Dominant-negative cdk3 inhibited E2F-1, E2F-2, and, less significantly, E2F-3, but not E2F-4 transcription activity. The inhibition occurred in a pRb-independent manner and did not affect the DNA-binding capacity of the transcription factor. Cdk3 bound specifically to E2F-1/DP-1 complexes in vivo, most likely through DP-1. Thus, cdk3 function contributes to the activation of E2F-1, E2F-2, and partially E2F-3 and, thereby, participates in the process of S-phase entry.
Mesh Terms:
Antigens, Viral, Tumor, Base Sequence, CDC2-CDC28 Kinases, Carrier Proteins, Cell Cycle Proteins, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 3, Cyclin-Dependent Kinases, DNA-Binding Proteins, E2F Transcription Factors, E2F1 Transcription Factor, E2F3 Transcription Factor, G1 Phase, Gene Expression Regulation, Genes, Reporter, Interphase, Models, Genetic, Molecular Sequence Data, Mutation, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Proteins, Retinoblastoma Protein, Retinoblastoma-Binding Protein 1, S Phase, Simian virus 40, Transcription Factor DP1, Transcription Factors, Transcription, Genetic
Antigens, Viral, Tumor, Base Sequence, CDC2-CDC28 Kinases, Carrier Proteins, Cell Cycle Proteins, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 3, Cyclin-Dependent Kinases, DNA-Binding Proteins, E2F Transcription Factors, E2F1 Transcription Factor, E2F3 Transcription Factor, G1 Phase, Gene Expression Regulation, Genes, Reporter, Interphase, Models, Genetic, Molecular Sequence Data, Mutation, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Proteins, Retinoblastoma Protein, Retinoblastoma-Binding Protein 1, S Phase, Simian virus 40, Transcription Factor DP1, Transcription Factors, Transcription, Genetic
Genes Dev.
Date: Apr. 01, 1996
PubMed ID: 8846921
View in: Pubmed Google Scholar
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