Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression

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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.