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

AUTOR(ES)

He, Liusheng

FONTE

Oxford University Press

RESUMO

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.

Documentos Relacionados

• Possible function of the c-myc product: promotion of cellular DNA replication.
• Posttranscriptional regulation of cellular gene expression by the c-myc oncogene.
• Psoralen-modified clamp-forming antisense oligonucleotides reduce cellular c-Myc protein expression and B16-F0 proliferation
• Human promyelocytic leukemia HL-60 cell proliferation and c-myc protein expression are inhibited by an antisense pentadecadeoxynucleotide targeted against c-myc mRNA.
• Metabolism of c-myc gene products: c-myc mRNA and protein expression in the cell cycle.