Jason Matthews, Ph.D.

Associate Professor General Area of Research: Molecular Pharmacology and Toxicology Receptor-mediated Modulation of Gene Expression by Aryl Hydrocarbon Receptor and Estrogen Receptors

My laboratory focuses on understanding transcriptional regulation by nuclear proteins the molecular mechanisms whereby the halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene. These compounds are in some case extremely toxic environmental contaminants that humans are exposed through diet, lifestyle and accidental exposures. These contaminants bind and activate the aryl hydrocarbon receptor (AHR) which modulates gene expression and alters cell proliferation and differentiation. The AHR is expressed in all mammalian species, including humans, possess the AHR, but despite this conservation the function of this protein in basic cell regulatory processes remains to be defined.

Much of the research in the lab is focused on understanding the mechanism of AHR action. We are interested in understanding its interactions with DNA, the mechanisms whereby it modulates gene expression in a context-, tissue- and cell-specific manner. To this end, we study the molecular mechanisms by which environmental and dietary chemicals bind to the AHR and act as agonists or antagonists. In addition, more recent studies have focused on identifying signaling molecules that regulate AHR function. We are also very interested in determining the biological role for the well-documented functional crosstalk between activated AHR and other transcription factors. Recent data from our group show that in the absence of estrogen AHR ligands, acting through the AHR, modulate estrogen receptor α (ERα) activity causing ERα to be recruited to, and become part of, the transcriptionally-active AHR complex present on AHR-regulated target genes. Understanding ERα signalling in the context of AHR activation and how this may impact human diseases is a research area that we also investigate. Our research involves the use of molecular biological, functional genomic and proteomic approaches, as well as genetically modified mouse models to study AHR-dependent signalling. Using ChIP-chip methodologies we have identified a number of AHR target genes that are also bound by ERα.

Selected Publications:

Celius, T and Matthews, J. (SRA) (2010) Functional analysis of six aryl hydrocarbon receptor variants in human breast cancer and mouse hepatoma cell lines. Toxicology 277, 59-65.

MacPherson. L. and Matthews, J.. (2010) Inhibition of AHR-dependent transcription by resveratrol or kaempferol is independent of estrogen receptor alpha in T-47D human breast cancer cells. Cancer Lett, 299, 119-129.

Pansoy, A., Ahmed, S., Valen, E., Sandelin, A., and Matthews, J. (2010) 3-methylcholanthrene-induces differential recruitment of aryl hydrocarbon receptor to human promoters. Toxicol Sci 117, 90–100.

Lo, R., Burgoon, L., MacPherson, L., Ahmed, S. and Matthews, J. (2010) Estrogen receptor and estrogen dependent regulation of CYP2B6 in human breast cancer cells. BBA Gen Regulatory Mechanisms. 1799, 469-479.

Ahmed, S, Valen, E., Sandelin, A., and Matthews, J. (2009). Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters. Toxicol Sci 111, 254-266.

Wihlén, B., Ahmed, S., Inzunza, J., and Matthews, J. (2009) Estrogen receptor subtype- and promoter-specific modulation of aryl hydrocarbon receptor transactivation. Mol Cancer Res 7, 977-986.

MacPherson, L., Lo, R., Ahmed, S, Pansoy, P., and Matthews, J. (2009) Activation Function 2 mediates dioxin-induced recruitment of estrogen receptor alpha to CYP1A1 and CYP1B1. Biochem Biophys Res Comm 385, 263-268.

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).

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, 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.

Contact Address: University of Toronto
Department of Pharmacology and Toxicology 
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