Regulation of the cdk inhibitor p21 gene during cell cycle progression is under the control of the transcription factor E2F.
The control of cell cycle progression is orchestrated by an extraordinary diverse and dynamic in function group of proteins. Critical in the progression are the actions of the E2F family of transcription factors which regulate the expression of genes necessary for the G1/S transition and the WAF/CIP/KIP family of cdk inhibitors which can inhibit cell cycle progression. In this report, we have identified E2F binding sites in both the human and mouse p21 promoters that bind E2F protein complexes from nuclear extracts in a cell cycle-dependent manner. In ectopic expression experiments we determined that E2F1, but not E2F4, can strongly transactivate the human p21 gene through these E2F binding sites which are located in the -215/+1 region of the p21 gene. The transactivation of the p21 gene through regulatory elements within the -215/+1 region of the promoter was correlated with increased levels of endogenous E2F1 and p21 proteins at the G1/S boundary. The significance of transactivation of the p21 gene by E2F is that p21 function is important in cell cycle progression as well as for cell cycle arrest. Indeed, E2F-induced levels of p21 protein during the G1/ S transition is consistent with the recent findings demonstrating that p21 acts as an assembly factor for kinase active cyclin/cdk/p21 complexes.
Hiyama
H
H
Molecular Neuro-Oncology, Neuroscience Center, Massachusetts General Hospital, Boston 02129, USA.
Iavarone
A
A
Reeves
S A
SA
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050704:E2F4 Transcription Factor; D004791:Enzyme Inhibitors / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000235:genetics; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
C533431:Arid4a protein, mouse; C493956:CDKN1A protein, human; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; C493754:E2f1 protein, mouse; C493763:E2f4 protein, mouse; D004791:Enzyme Inhibitors; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors