ToxSci Advance Access published online on October 8, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn217
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles of Coactivator Proteins in Dioxin Induction of CYP1A1 and CYP1B1 in Human Breast Cancer Cells
Molecular Toxicology Program (R.T.T., E.L.H., O.H.), Department of Pathology and Laboratory Medicine, and the Jonsson Comprehensive Cancer Center (R.T.T., F.W., E.L.H., O.H.) University of California, Los Angeles, CA 90095
Oliver Hankinson, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Center for the Health Sciences, UCLA, Box 951732, Los Angeles, CA 90095-1732, Tel: (310) 825-2936, Fax: (310) 794-9272, ohank{at}mednet.ucla.edu
Received September 10, 2008; revision received October 2, 2008; accepted October 2, 2008
 |
Abstract |
|---|
CYP1A1 and CYP1B1 are inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in the human breast cancer cell line, MCF-7. Since CYP1A1 was inducible to a much greater degree than CYP1B1, we hypothesized that there may be differences in coactivator recruitment to the promoter and/or enhancer regions of these genes. . Dioxin treatment lead to recruitment of the aryl hydrocarbon receptor (AHR) to the enhancer regions, but not to the proximal promoter regions of both the CYP1A1 and CYP1B1 genes. On the other hand, dioxin treatment facilitated recruitment of RNA polymerase II (pol II) to the promoters, but not the enhancer regions. Dioxin treatment also elicited recruitment of the transcriptional coactivators, Steriod Receptor Coactivators 1 and 2 (SRC-1 and SRC-2) and p300, which possess intrinsic histone acetyltranferase activities, to both genes, whereas Brahma SWI2/related gene 1 (BRG-1), a subunit of nucleosomal remodeling factors, was recruited more robustly to CYP1A1 relative to CYP1B1. SiRNA-mediated knock-down of p300 and SRC-2 adversely affected dioxin induction of both genes, whereas knock-down of Brahma/BRG-1 reduced CYP1A1 induction but had little, if any, effect on CYP1B1 induction. These results suggest that nucleosomal remodeling is less significant for dioxin-mediated induction of CYP1B1 than that of CYP1A1 and may be related to the more modest inducibility of the former. Interestingly, simultaneous knock-down of SRC-2 and Brahma/BRG-1 had no greater effect on CYP1A1 induction than knock-down of each coactivator individually, while simultaneous knock-down of p300 and Brahma/BRG-1 had a much greater effect than knock-down of each individual gene, suggesting that the recruitment of SRC-2 to CYP1A1 depends upon Brahma/BRG-1, while the recruitments of p300 and Brahma/BRG-1 are independent of each other. These observations provide novel insights into the functional roles of the endogenous coactivators in dioxin induction of the human CYP1A1 and CYP1B1 genes in their natural chromosomal configurations.
Key Words: CYP1A1; CYP1B1; Aryl Hydrocarbon Receptor; transcription; coactivator.
* Current address: CellzDirect Invitrogen Corporation,1624 Headway Circle, Austin, TX 78754. Rob.Taylor{at}invitrogen.com
+ Current address: Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 10-258, Chicago, IL 60611. e-hsu{at}northwestern.edu, (FWang{at}mednet.ucla.edu)
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. R. Beedanagari, I. Bebenek, P. Bui, and O. Hankinson Resveratrol Inhibits Dioxin-Induced Expression of Human CYP1A1 and CYP1B1 by Inhibiting Recruitment of the Aryl Hydrocarbon Receptor Complex and RNA Polymerase II to the Regulatory Regions of the Corresponding Genes Toxicol. Sci., July 1, 2009; 110(1): 61 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Hankinson Repression of Aryl Hydrocarbon Receptor Transcriptional Activity by Epidermal Growth Factor Mol. Interv., June 1, 2009; 9(3): 116 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. H. Sutter, H. Yin, Y. Li, J. S. Mammen, S. Bodreddigari, G. Stevens, J. A. Cole, and T. R. Sutter EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes PNAS, March 17, 2009; 106(11): 4266 - 4271. [Abstract] [Full Text] [PDF]
|
|