BRCA1 modulates xenobiotic stress-inducible gene expression by interacting with ARNT in human breast cancer cells

Kang, Hyo Jin, Kim, Hee Jeong, Kim, Sang Keun, Barouki, Robert, Cho, Chi-Heum, Khanna, Kum Kum, Rosen, Eliot M. and Bae, Insoo (2006) BRCA1 modulates xenobiotic stress-inducible gene expression by interacting with ARNT in human breast cancer cells. The Journal of Biological Chemistry., 281 21: 14654-14662. doi:10.1074/jbc.M601613200

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Author Kang, Hyo Jin
Kim, Hee Jeong
Kim, Sang Keun
Barouki, Robert
Cho, Chi-Heum
Khanna, Kum Kum
Rosen, Eliot M.
Bae, Insoo
Title BRCA1 modulates xenobiotic stress-inducible gene expression by interacting with ARNT in human breast cancer cells
Journal name The Journal of Biological Chemistry.   Check publisher's open access policy
ISSN 0021-9258
Publication date 2006-05
Sub-type Article (original research)
DOI 10.1074/jbc.M601613200
Open Access Status File (Publisher version)
Volume 281
Issue 21
Start page 14654
End page 14662
Total pages 9
Place of publication Bethesda, MD, U.S.
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 06 Biological Sciences
0601 Biochemistry and Cell Biology
Abstract Previously, we have reported that BRCA1 regulates the expression of various classes of genes, including genes involved in xenobiotic stress responses (Bae, I., Fan, S., Meng, Q., Rih, J. K., Kim, H. J., Kang, H. J., Xu, J., Goldberg, I. D., Jaiswal, A. K., and Rosen, E. M. (2004) Cancer Res. 64, 7893–7909). In the present study, we have investigated the effects of BRCA1 on xenobiotic stress-inducible gene expression. In response to aryl hydrocarbon receptor (AhR) ligands, cytoplasmic AhR becomes activated and then translocates to the nucleus where it forms a complex with the aryl hydrocarbon receptor nuclear translocator (ARNT). Subsequently, the AhR·ARNT complex binds to the enhancer or promoter of genes containing a xenobiotic stress-responsive element and regulates the expression of multiple target genes including cytochrome P450 subfamily polypeptide 1 (CYP1A1). In this study, we have found that endogenous and overexpressed exogenous wild-type BRCA1 affect xenobiotic stress-induced CYP1A1 gene expression. Using a standard chromatin immunoprecipitation assay, we have demonstrated that BRCA1 is recruited to the promoter regions of CYP1A1 and CYP1B1 along with ARNT and/or AhR following xenobiotic exposure. Our findings suggest that BRCA1 may be physiologically important for mounting a normal response to xenobiotic insults and that it may function as a coactivator for ARNT activity. Using immunoprecipitation, Western blotting, and glutathione S-transferase capture assays, a xenobiotic-independent interaction between BRCA1 and ARNT has been identified, although it is not yet known whether this is a direct or indirect interaction. We have also found that the inducibility of CYP1A1 and CYP1B1 transcripts following xenobiotic stress was significantly attenuated in BRCA1 knockdown cells. This reduced inducibility is associated with an altered stability of ARNT and was almost completely reversed in cells transfected with an ARNT expression vector. Finally, we have found that xenobiotic (TCDD) treatments of breast cancer cells containing reduced levels of BRCA1 cause the transcription factor ARNT to become unstable.
Keyword Brca1
Breast cancer
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
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