title: Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.
abstract: Cdc6 has a critical regulatory role in the initiation of DNA replication in yeasts, but its function in mammalian cells has not been characterized. We show here that Cdc6 is expressed selectively in proliferating but not quiescent mammalian cells, both in culture and within tissues of intact animals. During the transition from a growth-arrested to a proliferative state, transcription of mammalian Cdc6 is regulated by E2F proteins, as revealed by a functional analysis of the human Cdc6 promoter and by the ability of exogenously expressed E2F proteins to stimulate the endogenous Cdc6 gene. Immunodepletion of Cdc6 by microinjection of anti-Cdc6 antibody blocks initiation of DNA replication in a human tumor cell line. We conclude that expression of human Cdc6 is regulated in response to mitogenic signals though transcriptional control mechanisms involving E2F proteins, and that Cdc6 is required for initiation of DNA replication in mammalian cells.
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yan
authors.forename: J
authors.initials: J
authors.lastname: DeGregori
authors.forename: R
authors.initials: R
authors.lastname: Shohet
authors.forename: G
authors.initials: G
authors.lastname: Leone
authors.forename: B
authors.initials: B
authors.lastname: Stillman
authors.forename: J R
authors.initials: JR
authors.lastname: Nevins
authors.forename: R S
authors.initials: RS
authors.lastname: Williams
mesh_terms: D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004261:DNA Replication; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction / Q000235:genetics*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C533431:Arid4a protein, mouse; C103706:CDC6 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors