Regulation of E2F-1 gene expression by p130 (Rb2) and D-type cyclin kinase activity.
Previous experiments have demonstrated that the regulation of E2F-1 transcription factor activity is critical for the maintenance of normal cell proliferation control. Regulation of E2F-1 is accomplished through at least two mechanisms: posttranslational regulation by binding proteins such as Rb and transcriptional regulation of the E2F-1 gene. The E2F-1 gene promoter has recently been isolated to examine this latter aspect of E2F-1 regulation. Preliminary studies demonstrate that the E2F-1 promoter is under E2F-dependent negative control during the cell growth response, being transcriptionally repressed through E2F sites in G0 and early G1. We now demonstrate that the presence of an E2F DNA-binding complex containing the Rb-related p130 protein (Rb2) correlates with E2F-1 gene repression and that overexpression of p130 inhibits transcription from the E2F-1 promoter. Moreover, D-type cyclin-dependent kinase activity specifically activates the E2F-1 promoter by relieving E2F-mediated repression but is inhibited by coexpression of the cdk4 and cdk6 inhibitor p16 (CDKN2, MTS1, INK4). Taken together, these findings suggest that E2F-1 gene expression is controlled during cell cycle progression by a regulatory network involving at least one oncogene (cyclin D1) and several potential tumor suppressor genes.
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division; D002460:Cell Line; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000378:metabolism*; D016213:Cyclins / Q000096:biosynthesis / Q000378:metabolism*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005786:Gene Expression Regulation; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins / Q000096:biosynthesis; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D009838:Oligodeoxyribonucleotides; D015513:Oncogene Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases