Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1.
The oncoprotein cyclin D1 binds to and activates cyclin-dependent kinase 4 (cdk4), whose activity is inhibited by p16INK4, the product of the putative tumor suppressor gene MTS1. Cyclin D1 controls the timing of S phase onset in mammalian cells. We show that cyclin D1 acts as a positive regulator of the transcription factor E2F. In particular, cyclin D1 overexpression leads to the activation of the dihydrofolate reductase (DHFR) gene promoter. Activation depends on the E2F binding site in the DHFR promoter, known to mediate its activation at the G1/S transition in vivo. Cyclin D1 can also activate the adenovirus E2 promoter via E2F. Both promoters are repressed by p16INK4 and this repression can be released by overexpression of cdk4. The data reported here support a direct role for cyclin D1 and its associated kinase in cell cycle regulation of E2F activity and S phase-specific gene expression. In addition, we show that both E2F sites bind complexes containing the retinoblastoma protein (pRB) and that in RB-deficient cell lines overexpression of cyclin D1 fails to activate E2F-dependent transcription, indicating that pRB may be involved in promoter activation.
Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Heidelberg, Germany.
A
A
Schulze
K
K
Zerfass
D
D
Spitkovsky
B
B
Henglein
P
P
Jansen-Dürr
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016147:Genes, Tumor Suppressor; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D015513:Oncogene Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000235:genetics; D056465:Retinoblastoma-Binding Protein 1; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009838:Oligodeoxyribonucleotides; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019938:Cyclin D1; D013762:Tetrahydrofolate Dehydrogenase; D017346:Protein Serine-Threonine Kinases; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases