DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter.
The Cdc25C phosphatase mediates cellular entry into mitosis. The cdc25C gene is a target for transcriptional downregulation by the tumor suppressor protein p53, and this repression can be shown to contribute to p53-dependent cell cycle arrest. Two independent mechanisms have been identified. One involves the direct binding of p53 to a site in the cdc25C promoter, and the second involves a CDE/CHR element. Both of these mediate p53-dependent repression at levels of p53 comparable to those produced by DNA damage. Three CCAAT elements in the cdc25C promoter that were previously implicated in p53-dependent repression fail to do so at physiologically relevant levels of p53. Repression of Cdc25C by p53 represents an additional mechanism for p53-dependent cell cycle arrest in response to DNA damage. Importantly, this is a clear demonstration of p53-mediated transcriptional downregulation that is dependent on sequence-specific DNA binding by p53.
St Clair
Selvon
S
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
Giono
Luciana
L
Varmeh-Ziaie
Shohreh
S
Resnick-Silverman
Lois
L
Liu
Wen-Jun
WJ
Padi
Abhilash
A
Dastidar
Jayasri
J
DaCosta
Andrea
A
Mattia
Melissa
M
Manfredi
James J
JJ
D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D003001:Cloning, Molecular; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D017930:Genes, Reporter; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013752:Tetracycline / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000737:chemistry* / Q000378:metabolism
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D004247:DNA; D011392:Proline; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D006655:Histone Deacetylases; D013752:Tetracycline