Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis

Abstract

Most effects of exposure to halogenated and polycyclic aromatic hydrocarbons are mediated by the aryl hydrocarbon receptor (AHR). It has long been recognized that the AHR is a ligand-activated transcription factor that plays a central role in the induction of drug-metabolizing enzymes and hence in xenobiotic detoxification. Of late, it has become evident that outside this well-characterized role, the AHR also functions as a modulator of cellular signaling pathways. In this Prospect, we discuss the involvement of the AHR in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, and the functions of the RB protein. Ultimately, the toxicity of AHR xenobiotic ligands may be intrinsically connected with the perturbation of these pathways and depend on the many critical signaling pathways and effectors with which the AHR itself interacts. J. Cell. Biochem. 96: 1174Biochem. 96: -1184Biochem. 96: , 2005. Key words: Ah receptor; xenobiotic ligands; signal transduction; retinoblastoma protein; apoptosis Exposure to halogenated aromatic hydrocarbons (HAHs) and PAHs results in a wide range of toxic and carcinogenic responses in animals and in humans. It is widely accepted that most of these exposure effects are mediated by the aryl hydrocarbon receptor (AHR), a cytosolic ligand-activated transcription factor that upon ligand binding translocates to the nucleus, where it complexes with ARNT (a.k.a. HIF1b). AHR/ARNT heterodimers bind to specific consensus DNA sites in the regulatory domains of genes coding for many Phase I and Phase II drug-metabolizing enzymes and activate the transcription of these genes [Hankinson, 1995]. During the last 8-10 years, it has also become evident that the AHR has a second function, involving promotion of cell cycle progression, and that this function is accomplished in the absence of an exogenous ligand. In contrast, activation of the Ah receptor by high-affinity HAH or PAH ligands such as TCDD and B[a]P has been known for many years to result in a wide range of cell cycle perturbations, including G 0 /G 1 and G 2 /M arrest, diminished capacity for DNA replication, and inhibition of cell proliferation [reviewed in Puga et al., 2002]. These two outcomes are diametrically opposed and raise questions for which we do not have satisfactory answers at present. For example, how does the unliganded cytosolic Ah receptor influence a nuclear function such as cell cycle progression? Does this effect involve nuclear translocation? If so, do liganded and unliganded nuclear translocation events have different molecular outcomes? What makes dioxin carcinogenic? In these and similar questions, we need to bear in mind that it is only our current ß 2005 Wiley-Liss, Inc.

Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR

“…The role of miR-124 is not only critical in the neuronal development, but also in tumorigenesis. Recently, many reports show that AHR possesses anti-cancer effects [25,26]. These studies support our findings that inhibition of miR-124 caused increasing in AHR and resulted in cell differentiation.…”

“…4A). Since AHR has been shown to promote neuroblastoma cell differentiation [18,25,26], it is plausible that miR-124 may affect neuroblastoma cell differentiation by targeting on AHR. To demonstrate whether there was a direct targeting of AHR by miR-124, Pre was cotransfected with a luciferase reporter plasmid carrying 3 0 -UTR of AHR in the form of wild type (WT), mutation in the first four miR-124 targeting site (mut), and deletion of the seed region binding site (del) (Fig.…”

Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

“…The wide range of toxic effects induced by these compounds, including birth defects, impaired reproductive capacity and altered immune responses, have encouraged research on the interaction of AhR with sex steroid receptors and the immune system (Ohtake et al, 2008;Quintana et al, 2008;Veldhoen et al, 2008). AhR regulates cellular differentiation during development (Huang et al, 2004;Lahvis et al, 2000) and may promote cell cycle progression in the absence of exogenous ligand (Chang et al, 2007;Marlowe and Puga, 2005). There is also an emerging evidence for a prominent role of AhR in tumorigenesis.…”

Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

“…Aryl hydrocarbon receptor interacting protein is best characterised through its cytoplasmic interaction with the AHR (Carver and Bradfield, 1997), a transcription factor that regulates many xenobiotic metabolising enzymes (Meyer and Perdew, 1999;Marlowe and Puga, 2005). Aryl hydrocarbon receptor interacting protein modulates the stability and subcellular localisation of AHR by preventing its dynamic nucleocytoplasmic shuttling (Pollenz and Dougherty, 2005).…”