Novel activation domain derived from Che-1 cofactor coupled with the artificial protein Jazz drives utrophin upregulation

Neuromuscul Disord. 2009 Feb;19(2):158-62. doi: 10.1016/j.nmd.2008.11.005. Epub 2009 Jan 21.

Abstract

Our aim is to upregulate the expression level of the dystrophin related gene utrophin in Duchenne muscular dystrophy, thus complementing the lack of dystrophin functions. To this end, we have engineered synthetic zinc finger based transcription factors. We have previously shown that the artificial three-zinc finger protein named Jazz fused with the Vp16 activation domain, is able to bind utrophin promoter A and to increase the endogenous level of utrophin in transgenic mice. Here, we report on an innovative artificial protein, named CJ7, that consists of Jazz DNA binding domain fused to a novel activation domain derived from the regulatory multivalent adaptor protein Che-1/AATF. This transcriptional activation domain is 100 amino acids in size and it is very powerful as compared to the Vp16 activation domain. We show that CJ7 protein efficiently promotes transcription and accumulation of the acetylated form of histone H3 on the genomic utrophin promoter locus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Apoptosis Regulatory Proteins / genetics*
  • Binding Sites / genetics
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Genetic Therapy / methods
  • HeLa Cells
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Peptides / chemical synthesis
  • Peptides / genetics
  • Peptides / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Engineering
  • Protein Structure, Tertiary / genetics
  • Repressor Proteins / genetics*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcriptional Activation / genetics
  • Up-Regulation / genetics*
  • Utrophin / genetics*
  • Utrophin / metabolism

Substances

  • AATF protein, human
  • Apoptosis Regulatory Proteins
  • CJ7 protein
  • DNA-Binding Proteins
  • Histones
  • Peptides
  • Repressor Proteins
  • Transcription Factors
  • Utrophin