title: Transcriptional control of DNA replication licensing by Myc.
abstract: The c-myc protooncogene encodes the Myc transcription factor, a global regulator of fundamental cellular processes. Deregulation of c-myc leads to tumorigenesis, and c-myc is an important driver in human cancer. Myc and its dimerization partner Max are bHLH-Zip DNA binding proteins involved in transcriptional regulation of target genes. Non-transcriptional functions have also been attributed to the Myc protein, notably direct interaction with the pre-replicative complex (pre-RC) controlling the initiation of DNA replication. A key component of the pre-RC is the Cdt1 protein, an essential factor in origin licensing. Here we present data suggesting that the CDT1 gene is a transcriptional target of the Myc-Max complex. Expression of the CDT1 gene in v-myc-transformed cells directly correlates with myc expression. Also, human tumor cells with elevated c-myc expression display increased CDT1 expression. Occupation of the CDT1 promoter by Myc-Max is demonstrated by chromatin immunoprecipitation, and transactivation by Myc-Max is shown in reporter assays. Ectopic expression of CDT1 leads to cell transformation. Our results provide a possible direct mechanistic link of Myc's canonical function as a transcription factor to DNA replication. Furthermore, we suggest that aberrant transcriptional activation of CDT1 by deregulated myc alleles contributes to the genomic instabilities observed in tumor cells.
authors.affiliation: Institute of Biochemistry, Center for Molecular Biosciences, University of Innsbruck, Austria.
authors.forename: Taras
authors.initials: T
authors.lastname: Valovka
authors.forename: Manuela
authors.initials: M
authors.lastname: Schönfeld
authors.forename: Philipp
authors.initials: P
authors.lastname: Raffeiner
authors.forename: Kathrin
authors.initials: K
authors.lastname: Breuker
authors.forename: Theresia
authors.initials: T
authors.lastname: Dunzendorfer-Matt
authors.forename: Markus
authors.initials: M
authors.lastname: Hartl
authors.forename: Klaus
authors.initials: K
authors.lastname: Bister
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002645:Chickens; D004261:DNA Replication; D005786:Gene Expression Regulation; D023061:Gene Order; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc