title: Genomic analysis of wig-1 pathways.
abstract: BACKGROUND
  Wig-1 is a transcription factor regulated by p53 that can interact with hnRNP A2/B1, RNA Helicase A, and dsRNAs, which plays an important role in RNA and protein stabilization. in vitro studies have shown that wig-1 binds p53 mRNA and stabilizes it by protecting it from deadenylation. Furthermore, p53 has been implicated as a causal factor in neurodegenerative diseases based in part on its selective regulatory function on gene expression, including genes which, in turn, also possess regulatory functions on gene expression. In this study we focused on the wig-1 transcription factor as a downstream p53 regulated gene and characterized the effects of wig-1 down regulation on gene expression in mouse liver and brain.
  
  
  RESULTS
  Antisense oligonucleotides (ASOs) were identified that specifically target mouse wig-1 mRNA and produce a dose-dependent reduction in wig-1 mRNA levels in cell culture. These wig-1 ASOs produced marked reductions in wig-1 levels in liver following intraperitoneal administration and in brain tissue following ASO administration through a single striatal bolus injection in FVB and BACHD mice. Wig-1 suppression was well tolerated and resulted in the reduction of mutant Htt protein levels in BACHD mouse brain but had no effect on normal Htt protein levels nor p53 mRNA or protein levels. Expression microarray analysis was employed to determine the effects of wig-1 suppression on genome-wide expression in mouse liver and brain. Reduction of wig-1 caused both down regulation and up regulation of several genes, and a number of wig-1 regulated genes were identified that potentially links wig-1 various signaling pathways and diseases.
  
  
  CONCLUSIONS
  Antisense oligonucleotides can effectively reduce wig-1 levels in mouse liver and brain, which results in specific changes in gene expression for pathways relevant to both the nervous system and cancer.
authors.affiliation: Department of Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, California, United States of America.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Sedaghat
authors.forename: Curt
authors.initials: C
authors.lastname: Mazur
authors.forename: Mahyar
authors.initials: M
authors.lastname: Sabripour
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
mesh_terms: D000818:Animals; D001921:Brain; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D023281:Genomics; D008099:Liver; D051379:Mice; D009369:Neoplasms; D009420:Nervous System; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C436503:ZMAT3 protein, human