Specific regulation of E2F family members by cyclin-dependent kinases.
The transcription factor E2F-1 interacts stably with cyclin A via a small domain near its amino terminus and is negatively regulated by the cyclin A-dependent kinases. Thus, the activities of E2F, a family of transcription factors involved in cell proliferation, are regulated by at least two types of cell growth ... regulators: the retinoblastoma protein family and the cyclin-dependent kinase family. To investigate further the regulation of E2F by cyclin-dependent kinases, we have extended our studies to include additional cyclins and E2F family members. Using purified components in an in vitro system, we show that the E2F-1-DP-1 heterodimer, the functionally active form of the E2F activity, is not a substrate for the active cyclin D-dependent kinases but is efficiently phosphorylated by the cyclin B-dependent kinases, which do not form stable complexes with the E2F-1-DP-1 heterodimer. Phosphorylation of the E2F-1-DP-1 heterodimer by cyclin B-dependent kinases, however, did not result in down-regulation of its DNA-binding activity, as is readily seen after phosphorylation by cyclin A-dependent kinases, suggesting that phosphorylation per se is not sufficient to regulate E2F DNA-binding activity. Furthermore, heterodimers containing E2F-4, a family member lacking the cyclin A binding domain found in E2F-1, are not efficiently phosphorylated or functionally down-regulated by cyclin A-dependent kinases. However, addition of the E2F-1 cyclin A binding domain to E2F-4 conferred cyclin A-dependent kinase-mediated down-regulation of the E2F-4-DP-1 heterodimer. Thus, both enzymatic phosphorylation and stable physical interaction are necessary for the specific regulation of E2F family members by cyclin-dependent kinases.
Mesh Terms:
CDC2-CDC28 Kinases, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cell-Free System, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, Cyclins, DNA-Binding Proteins, E2F Transcription Factors, E2F1 Transcription Factor, Peptide Mapping, Phosphopeptides, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Proteins, Retinoblastoma-Binding Protein 1, Structure-Activity Relationship, Substrate Specificity, Transcription Factors
CDC2-CDC28 Kinases, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cell-Free System, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, Cyclins, DNA-Binding Proteins, E2F Transcription Factors, E2F1 Transcription Factor, Peptide Mapping, Phosphopeptides, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Proteins, Retinoblastoma-Binding Protein 1, Structure-Activity Relationship, Substrate Specificity, Transcription Factors
Mol. Cell. Biol.
Date: Jul. 01, 1997
PubMed ID: 9199321
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