BRCA1 transcriptional activity is enhanced by interactions between its AD1 domain and AhR

Hyo Jin Kang, Hee Jeong Kim, Chi Heum Cho, Yanfen Hu, Rong Li, Insoo Bae

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Purpose: 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 α-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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)965-975
Number of pages11
JournalCancer chemotherapy and pharmacology
Volume62
Issue number6
DOIs
StatePublished - Nov 1 2008

Keywords

  • AD1
  • AhR
  • BRCA1
  • JunB
  • Transcription regulation
  • Xenobiotic stress

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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