Inhibiton of growth by 2,3,7,8-terachlorodibezo-<i>p</i>-dioxin in 5L rat hepatoma cells is associated with the presence of Ah receptor

Göttlicher, Martin; Cikryt, Peter; Wiebel, Friedrich J.

doi:10.1093/carcin/11.12.2205

Cited by 35 publications

(13 citation statements)

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“…1C), indicating that TCDD acts primarily by promoting the accumulation of cells in G 1 and blocking progression from G 1 to S phase. Similar results have been obtained in the rat 5L hepatoma cell line, where the effect of TCDD on the cell cycle has been shown to be dependent on the presence of a functional AHR (64,65). These results confirm those in both this and other cell lines and indicate that the effect of AHR overexpression observed in transfection studies (44) is relevant to physiological conditions.…”

Section: Tcdd Inhibits S Phase Progression In Multiple Cell Lines-supporting

confidence: 87%

The Aryl Hydrocarbon Receptor Displaces p300 from E2F-dependent Promoters and Represses S Phase-specific Gene Expression

Marlowe

Knudsen

Schwemberger³

et al. 2004

Journal of Biological Chemistry

142

122

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The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic, teratogenic, and carcinogenic effects. TCDD is a ligand for the aromatic hydrocarbon receptor (AHR), a ligand-activated transcription factor believed to be the primary mediator of these effects. Activation of the AHR by TCDD also elicits a variety of effects on cell cycle progression, ranging from proliferation to arrest. In this report, we have characterized further the role of the activated AHR in cell cycle regulation. In human mammary carcinoma MCF-7 and mouse hepatoma Hepa-1 cells, TCDD treatment decreased the number of cells in S phase and caused the accumulation of cells in G 1 . In Hepa-1 cells, this effect correlated with the transcriptional repression of several E2F-regulated genes required for S phase progression. AHR-mediated gene repression was dependent on its interaction with retinoblastoma protein but was independent of its transactivation function because AHR mutants lacking DNA binding or transactivation domains repressed E2F-dependent expression as effectively as wild type AHR. Overexpression of p300 suppressed retinoblastoma protein-dependent gene repression, and this effect was reversed by TCDD. Chromatin immunoprecipitation assays showed that TCDD treatment caused the recruitment of AHR to E2F-dependent promoters and the concurrent displacement of p300. These results delineate a novel mechanism whereby the AHR, a known transcriptional activator, also mediates gene repression by pathways involving combinatorial interactions at E2F-responsive promoters, leading to the repression of E2F-dependent, S phase-specific genes. The AHR seems to act as an environmental checkpoint that senses exposure to environmental toxicants and responds by signaling cell cycle inhibition.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) 1 is the prototypical compound of a class of environmental contaminants that includes many halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons and is a model for the outcome of exposure to these compounds as well as coplanar polychlorinated biphenyls. Exposure to TCDD results in a plethora of toxic and carcinogenic responses in animals, including liver toxicity (1), immunosuppression (2, 3), reproductive and developmental dysfunction (4 -6), endometriosis (7,8), and tumor promotion (9). The most immediate exposure outcome in humans is chloracne (10). Long term effects in humans range from immunological and reproductive perturbations (11) to cardiovascular disease (12, 13) and cancer (14 -18). TCDD itself is poorly metabolized, which leads to biological accumulation and production of sustained effects (19).Although the in vivo effects of TCDD are wide ranging, the in vitro effects are just as varied and often contradictory, affecting cell proliferation, apoptosis, and differentiation, depending on the cell type examined. TCDD acts as an endocrine disruptor in cell cultures, inhibiting several estrogen-induced responses such as growth of human mammary and endometrial canc...

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Section: Tcdd Inhibits S Phase Progression In Multiple Cell Lines-supporting

confidence: 87%

The Aryl Hydrocarbon Receptor Displaces p300 from E2F-dependent Promoters and Represses S Phase-specific Gene Expression

Marlowe

Knudsen

Schwemberger³

et al. 2004

Journal of Biological Chemistry

142

122

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“…This effect has since been extended to MCF-7 breast cancer cells (Gierthy et al 1993), rat H4IIE hepatoma cells (Gottlicher et al 1990), rat livers (Fox et al 1993) and primary rat hepatocytes (Hushka and Greenlee 1995).…”

Section: Ahr Ligands and Cell Cycle / Cell Proliferationmentioning

confidence: 97%

“…Inhibition of proliferation in response to HAH treatment has been observed in vitro in a wide range of cell types, including epithelial cells (Gierthy et al 1984), MCF-7 breast cancer cells (Gierthy et al 1993), rat H4IIE hepatoma cells (Gottlicher et al 1990), rat livers (Fox et al 1993) and primary rat hepatocytes (Hushka et al 1995). However, stimulation of proliferation by TCDD has been observed in other experiments (Dickins et al 1981;Busser et al 1987;Wolfle et al 1988;Lucier et al 1991;Schrenk et al 1992), and evidence suggests that proliferative effects are dependent on cell type, time in culture and culture conditions.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of action for aryl hydrocarbon receptor ligands in the PLHC-1 cell line

Hestermann¹

1999

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“…This effect depends on the presence of the Ah receptor, since variant 5L clones lacking AHR expression do not show delayed G 1 to S progression [Gottlicher et al, 1990;Göttlicher and Wiebel, 1991;Wiebel et al, 1991], and expression of ectopic AHR in these variant cell lines reconstitutes the ability of TCDD to delay cell cycle progression [Weiss et al, 1996]. Several observations may explain these findings.…”

Section: Cell Cycle Arrest Induced By Ahr Ligandsmentioning

confidence: 99%

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

Marlowe

Puga

2005

J of Cellular Biochemistry

282

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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Inhibiton of growth by 2,3,7,8-terachlorodibezo-p-dioxin in 5L rat hepatoma cells is associated with the presence of Ah receptor

Cited by 35 publications

References 0 publications

The Aryl Hydrocarbon Receptor Displaces p300 from E2F-dependent Promoters and Represses S Phase-specific Gene Expression

The Aryl Hydrocarbon Receptor Displaces p300 from E2F-dependent Promoters and Represses S Phase-specific Gene Expression

Mechanisms of action for aryl hydrocarbon receptor ligands in the PLHC-1 cell line

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

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