Alex M.L. Wu

University of Toronto, Toronto, Ontario, Canada

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Publications (2)6.97 Total impact

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    ABSTRACT: Breast cancer resistance protein (BCRP/ABCG2) is a membrane-bound efflux transporter important in cellular detoxification and multidrug resistance. Some aryl hydrocarbon receptor (AHR) agonists were reported to induce BCRP expression in human colon carcinoma cells. However, a direct involvement of AHR transcriptional regulation remains unexplored. In this study, we show that BCRP induction by AHR ligands occurs in human intestinal, liver, and mammary carcinoma cells and in primary colonocytes and hepatocytes. Increased BCRP transporter activity consistent with gene induction was also evident in the Caco2 subclone C2bbe1 cells. Using RNA interference and ectopic expression techniques to manipulate cellular AHR status, we confirmed AHR dependence of ABCG2 gene regulation. By gene promoter analysis, chromatin immunoprecipitation, and electrophoretic mobility shift assays, an active, proximal dioxin-response element at -194/-190 base pairs upstream of the transcription start site of the human ABCG2 gene was identified. Despite a common observation in human-derived cells, our in vitro and in vivo studies supported by phylogenetic footprinting analysis did not find that mouse Abcg2 is subject to AHR regulation. We conclude that AHR is a direct transcriptional regulator of human BCRP and provide an unprecedented role of AHR in cellular adaptive response and cytoprotection by up-regulating an important ATP-binding cassette efflux transporter.
    No preview · Article · May 2010 · Molecular pharmacology
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    ABSTRACT: The canonical transient receptor potential type 3 (TRPC3) channel is a non-selective, voltage-independent cation channel that is expressed in both excitable and non-excitable cells. As little is known regarding its presence in human brain and the influence of age on its expression, we examined TRPC3 protein expression by immunoblotting in postmortem prefrontal cortex and cerebellum obtained from subjects (8 days to 83 years) with no history of psychiatric or neurological disorder. The expression of TRPC3 protein in the prefrontal cortex (Brodmann area A9/A10) of the neonates/infants (<2 y) was significantly higher (25%) than that in the adolescent to adult (11y-83y) age group, whereas cerebellar TRPC3 levels showed no age-related changes. The results indicate that TRPC3 may be developmentally regulated in prefrontal cortex, and its expression in discrete human brain regions throughout the lifespan suggests a physiological role for TRPC3 during postnatal and adult life.
    No preview · Article · Mar 2009 · Brain research