Multiple Mechanisms Are Involved in Ah Receptor-Mediated Cell Cycle Arrest

Huang, Gengming; Elferink, Cornelis

doi:10.1124/mol.104.002410

Cited by 93 publications

(73 citation statements)

References 48 publications

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“…Recent data from our laboratory [Marlowe et al, 2004] and from Elferink and colleagues [Huang and Elferink, 2005] have confirmed this conclusion. AHR activation in cycling Hepa-1c1c7 cells results in the accumulation of cells in G 1 [Marlowe et al, 2004].…”

Section: Cell Cycle Arrest Induced By Ahr Ligandssupporting

confidence: 73%

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

Marlowe

Puga

2005

J of Cellular Biochemistry

281

201

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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.

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Section: Cell Cycle Arrest Induced By Ahr Ligandssupporting

confidence: 73%

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

Marlowe

Puga

2005

J of Cellular Biochemistry

281

201

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“…Treatment of mouse hepatoma cells with a component of tobacco smoke [2,3,7,8-tetrachlorodibenzo- Daily use of supplements containing folic acid (400-500 g) from 4 weeks before conception of the child until 8 weeks after; incidental users and women who started folic acid supplements later than 4 weeks before conception were excluded c Any folic acid use during pregnancy, also incidental users and women who started folic acid supplements later than 4 weeks before conception were included resulted in the co-repression of E2F-mediated expression of genes necessary for cell cycle progression (Huang and Elferink 2005). Another interesting hypothesis is that AhR suppresses Tgfb3 expression and Tgfb3 has an indirect eVect on IRF6.…”

Section: Discussionmentioning

confidence: 99%

The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts

et al. 2008

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Nonsyndromic orofacial clefts (OFC) are common birth defects caused by certain genes interacting with environmental factors. Mutations and association studies indicate that the homeobox gene MSX1 plays a role in human clefting. In a Dutch case-control triad study (mother, father, and child), we investigated interactions between MSX1 and the parents' periconceptional lifestyle in relation to the risk of OFC in their oVspring. We studied 181 case-and 132 control mothers, 155 case-and 121 control fathers, and 176 case-and 146 control children, in which there were 107 case triads and 66 control triads. Univariable and multivariable logistic regression analyses were applied, and odds ratios (OR), 95% conWdence intervals (CI) were calculated. Allele 4 of the CA marker in the MSX1 gene, consisting of nine CA repeats, was the most common allele found in both the case and control triads. SigniWcant interactions were observed between allele 4 homozygosity of the child with maternal smoking (OR 2.7, 95% CI 1.1-6.6) and with smoking by both parents (OR 4.9, 95% CI 1.4-18.0). Allele 4 homozygosity in the mother and smoking showed a risk estimate of OR 3.2 (95% CI 1.1-9.0). If allele 4 homozygous mothers did not take daily folic acid supplements in the recommended periconceptional period, this also increased the risk of OFC for their oVspring (OR 2.8, 95% CI 1.1-6.7). Our Wndings show that, in the Dutch population, periconceptional smoking by both parents interacts with a speciWc allelic variant of MSX1 to signiWcantly increase OFC risk for their oVspring. Possible underlying mechanisms are discussed.

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“…The liver is the only solid organ known to be capable of regenerating organ mass in response to damage (Huang and Elferink, 2005). This is important given the role of the liver in metabolism of both endogenous and exogenous compounds.…”

Section: Introductionmentioning

confidence: 99%