title: Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression.
abstract: The c-myc regulatory region includes binding sites for a large set of transcription factors. The present studies demonstrate that in the absence of FBP [far upstream element (FUSE)-binding protein], which binds to the single-stranded FUSE, the remainder of the set fails to sustain endogenous c-myc expression. A dominant-negative FBP DNA-binding domain lacking effector activity or an antisense FBP RNA, expressed via replication-defective adenovirus vectors, arrested cellular proliferation and extinguished native c-myc transcription from the P1 and P2 promoters. The dominant-negative FBP initially augmented the single-stranded character of FUSE; however, once c-myc expression was abolished, melting at FUSE could no longer be supported. In contrast, with antisense FBP RNA, the single-stranded character of FUSE decreased monotonically as the transcription of endogenous c-myc declined. Because transcription is the major source of super-coiling in vivo, we propose that by binding torsionally strained DNA, FBP measures promoter activity directly. We also show that FUSE is predicted to behave as a torsion-regulated switch poised to regulate c-myc and to confer a higher order regulation on a large repertoire of factors.
authors.affiliation: Laboratory of Pathology, DCS, NCI, Building 10, Room 2N105, Bethesda, MD 20892-1500, USA.
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: I
authors.initials: I
authors.lastname: Collins
authors.forename: S
authors.initials: S
authors.lastname: Sanford
authors.forename: B
authors.initials: B
authors.lastname: O'Connell
authors.forename: C J
authors.initials: CJ
authors.lastname: Benham
authors.forename: D
authors.initials: D
authors.lastname: Levens
mesh_terms: D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D016259:Genes, myc; D008969:Molecular Sequence Data; D016601:RNA-Binding Proteins
chemical_list: D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D016601:RNA-Binding Proteins; D004265:DNA Helicases