title: Indirect p53-dependent transcriptional repression of Survivin, CDC25C, and PLK1 genes requires the cyclin-dependent kinase inhibitor p21/CDKN1A and CDE/CHR promoter sites binding the DREAM complex.
abstract: The transcription factor p53 is central to cell cycle control by downregulation of cell cycle-promoting genes upon cell stress such as DNA damage. Survivin (BIRC5), CDC25C, and PLK1 encode important cell cycle regulators that are repressed following p53 activation. Here, we provide evidence that p53-dependent repression of these genes requires activation of p21 (CDKN1A, WAF1, CIP1). Chromatin immunoprecipitation (ChIP) data indicate that promoter binding of B-MYB switches to binding of E2F4 and p130 resulting in a replacement of the MMB (Myb-MuvB) by the DREAM complex. We demonstrate that this replacement depends on p21. Furthermore, transcriptional repression by p53 requires intact DREAM binding sites in the target promoters. The CDE and CHR cell cycle promoter elements are the sites for DREAM binding. These elements as well as the p53 response of Survivin, CDC25C, and PLK1 are evolutionarily conserved. No binding of p53 to these genes is detected by ChIP and mutation of proposed p53 binding sites does not alter the p53 response. Thus, a mechanism for direct p53-dependent transcriptional repression is not supported by the data. In contrast, repression by DREAM is consistent with most previous findings and unifies models based on p21-, E2F4-, p130-, and CDE/CHR-dependent repression by p53. In conclusion, the presented data suggest that the p53-p21-DREAM-CDE/CHR pathway regulates p53-dependent repression of Survivin, CDC25C, and PLK1.
authors.affiliation: Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.|Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Quaas
authors.affiliation: Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
authors.forename: Annina
authors.initials: A
authors.lastname: Nickel
authors.affiliation: Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Engeland
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017124:Conserved Sequence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D050704:E2F4 Transcription Factor / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism; D000077022:Survivin; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050704:E2F4 Transcription Factor; D051034:Inhibitor of Apoptosis Proteins; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D050717:Retinoblastoma-Like Protein p130; D000077022:Survivin; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D020687:cdc25 Phosphatases; D000097869:Polo-Like Kinase 1; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; C493762:E2F4 protein, human; C064352:MYBL2 protein, human; C495901:TP53 protein, human; C517009:CDC25C protein, human
keywords: CDE-CHR; CDKN1A; DREAM; p53; p53-p21-DREAM-CDE/CHR pathway