title: BRCA1 transcriptional activity is enhanced by interactions between its AD1 domain and AhR.
abstract: OBJECTIVE
  We previously reported that BRCA1 interacts with aryl hydrocarbon receptor nuclear translocator (ARNT) and that this interaction affects TCDD-induced CYP1A1 gene expression (Kang et al., J Biol Chem 281:14654-14662, 2006). In this study we continue this investigation and begin to define the significance of this interaction for the regulation of stress-induced transcription.
  
  
  METHODS
  Immunoprecipitations (IPs), western blot (WB) analysis, GST pull-down assays and promoter reporter assays were used to investigate whether the aryl hydrocarbon receptor (AhR) can regulate transcription that is dependent on the activation domain 1 (AD1) domain of BRCA1.
  
  
  RESULTS
  We show that AhR, a transcription factor, can bind specifically to AD1 in the C-terminal region of BRCA1 and affect BRCA1's ability to regulate transcription activity. We found that xenobiotics that positively and negatively affect AhR's activity as a transcription factor (e.g., dioxin and alpha-naphthoflavone, respectively), have similar effects on AhR's ability to affect AD1-domain-dependent transcription. These physical and functional AhR-AD1 interactions may require the coiled-coil motif in AD1 because point-mutations in this motif reduce these interactions.
  
  
  CONCLUSIONS
  Xenobiotic-activated AhR can function in two ways, as a component of the AhR/ARNT transcription factor and a regulator of AD1-dependent transcription. Consequently, BRCA1 has two distinct mechanisms for sensing xenobiotics and regulating AhR-dependent stress responses to these xenobiotics. We speculate that the normal functioning of this interaction could play a role in BRCA1's tumor suppressing ability.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057, USA.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Chi-Heum
authors.initials: CH
authors.lastname: Cho
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Hu
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Insoo
authors.initials: I
authors.lastname: Bae
mesh_terms: D019313:BRCA1 Protein / Q000737:chemistry* / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry* / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D001571:Benzoflavones; D009363:Neoplasm Proteins; D000072317:Polychlorinated Dibenzodioxins; D016755:Proto-Oncogene Proteins c-jun; D018336:Receptors, Aryl Hydrocarbon; C011512:alpha-naphthoflavone