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Assistant Professor
General Area of Research: Molecular Pharmacology and Toxicology
Molecular Mechanisms of AhR-dependent Transcription, and Crosstalk Between AhR and Estrogen Receptor Signalling Pathways |
The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor and member of the basic-helix-loop-helix Per (Period) – ARNT (aryl hydrocarbon nuclear translocator) – SIM (single minded) (bHLH-PAS) superfamily. The AhR mediates most, if not all, of the toxic effects of 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD). After binding ligand, the cytosolic form of AhR translocates to the nucleus where it binds its dimerization partner ARNT. The activated AhR/ARNT heterodimer complex binds to its cognate DNA sequences, termed xenobiotic response elements (XREs), resulting in the recruitment of coregulatory proteins, relaxation of chromatin structure and changes in transcription. The recent use of sophisticated molecular biological techniques has significantly increased our understanding of AhR-dependent transcription, and has highlighted the important role of chromatin in transcriptional regulation. However, the precise molecular details of the kinetics and the proteins/coregulators involved in the AhR-mediated transcription are not fully understood.
Crosstalk has been observed between activated AhR and other transcription factors, but is most well documented for estrogen receptors (ERs). The molecular basis for this crosstalk is unclear and is most likely a combination of several different mechanisms. Recent data from our group show that in the absence of estrogen AhR ligands, acting through the AhR, modulate ERα activity causing ERα to be recruited to, and become part of, the transcriptionally-active AhR complex present on AhR-regulated target genes. The recruitment of ERα to active AhR represents a new mechanism for AhR-dependent inhibition of ERα activity by sequestering ERα away from ERα target genes, but also supports a role for ERα in AhR transcription.
Research in my lab is focused on understanding the mechanisms of AhR-dependent transcription activation and repression. In addition, we are very interested in understanding the molecular mechanisms of crosstalk between AhR and ER signalling pathways. Our research involves the use of powerful molecular biological, functional genomic and proteomic approaches, and mouse models to study AhR-dependent transcription and elucidate the mechanisms of interplay between AhR and ER signalling. Characterizing the association of AhR and ERs will be important in uncovering the biological role of AhR and the role of ERs in AhR-mediated toxicity.
Selected Publications:
Matthews J, Wihlén B, Heldring N, Helguero L, Macpherson L, Treuter E, Haldosén L- A and Gustafsson J-Å. Coplanar 3,3’,4,4’,5-pentachlorinated biphenyl and non-coplanar 2,2’,4,6,6’-pentachlorinated biphenyl differentially induce recruitment of estrogen receptor α to aryl hydrocarbon receptor target genes. Biochemical J. 2007; 406:343-353 (corresponding author).
Zhao C, Matthews J, Tujague M, Wan J, Ström A, Toresson G, Lam E, Cheng G, Gustafsson J- Å and Dahlman-Wright K. Estrogen Receptor β2 Negatively Regulates the Transactivation of Estrogen Receptorα in Human Breast Cancer Cells. Cancer Res. 2007; 67:3955-3962.
Matthews J, Wihlén B, Strom A and Gustafsson J-Å. ERα modulates recruitment of AP-1 proteins during ERβ-mediated transcriptional activation. Mol Endocrinol. 2006 Mar; 20(3):534-43. Epub 2005 Nov 17 (corresponding author).
Matthews J, Almlöf T, Kietz S, Leers, J and Gustafsson, J-Å. Estrogen regulation of SOCS-3 in human breast cancer cells. Biochem Biophys Res. Commun. 2005; 335:168-174 (corresponding author).
Matthews J, Wihlén B, Thomsen J, and Gustafsson J-Å. Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor α to TCDD responsive promoters. Mol Cell Biol. 2005; 25:5317-5328.
Kietz S, Thomsen JS, Matthews J, Pettersson K, Ström A and Gustafsson J-Å. The AhR inhibits estrogen-induced estrogen receptor ß in breast cancer cells. Biochem Biophys Res Commun. 2004; 320:76-82.
Brunnberg S, Pettersson K, Rydin E, Matthews J, Hanberg A and Pongratz, I. The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription. Proc Natl Acad Sci USA. 2003; 100:6517-6522.
Matthews, J., Celius, C., Fertuk, K., Huang, Y-W., Fong, C., and Zacharewski, T.R. Ability of several natural and synthetic estrogenic chemicals to induce gene expression mediated by estrogen receptors from several vertebrate species. J Steroid Biochem and Mol Biol. 2002; 82:181-194.
Contact Address: University of Toronto
Department of Pharmacology
Room 4336, Medical Sciences Building
1 King's College Circle
Toronto, Ontario
M5S 1A8
Phone: [416]946-0851
FAX: [416]978-6395
Email: jason.matthews@utoronto.ca