Relationships among the cell cycle, cell proliferation, and aryl hydrocarbon receptor expression in PLHC-1 cells

Hestermann, Eli V.; Stegeman, John J.; Hahn, Mark E.

doi:10.1016/s0166-445x(01)00229-6

Cited by 19 publications

(6 citation statements)

References 62 publications

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“…of PLHC-1 cells (76), and in the estrogen-induced proliferation of MCF-7 cells (63), among others. Inhibition of cyclin-dependent kinase activities, inhibition of RB phosphorylation and induction of p27 Kip1 and p21 WAF1 have been observed and proposed as potential mechanisms responsible for the block.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…In mouse intrathymic progenitor cells, TCDD blocked Sphase progression and caused persistent thymic atrophy [Laiosa et al, 2003]. TCDD also inhibited proliferation of the fish hepatocellular carcinoma PLHC-1 cell line [Hestermann et al, 2002] and the androgen-induced proliferation of G 0 /G 1 -synchronized human prostate cancer LNCaP cells [Barnes-Ellerbe et al, 2004]. Treatment with TCDD also induced the AHRdependent G 1 arrest of SK-N-SH human neuronal cells concomitant with the increased expression of p27 and the hypophosphorylation of RB [Jin et al, 2004].…”

Section: Cell Cycle Arrest Induced By Ahr Ligandsmentioning

confidence: 98%

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

Marlowe

Puga

2005

J of Cellular Biochemistry

283

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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“…The data reveal about the relation between AhR transcriptional activity and the synchronization of the cells in M-phase of the cell cycle by microtubules disruption [75,76,97,98]. AhR interacts with the retinoblastoma protein (RB1), and the AhR-RB1 complex hinders progression from the G1 to the S phase of the cell cycle by blocking E2F transcription factor-mediated expression of S phase genes [15].…”

Section: The Role Of Microtubules Network In Cyp Genes Expressionmentioning

confidence: 99%

Role of Microtubules Network in CYP Genes Expression

Dvořák¹,

Ulrichová²,

Modrianský

2005

CDM

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Superfamily of cytochrome P450 enzymes (CYPs), a distinctive enzyme system by which human body defends itself against toxic compounds, is the subject of a complex regulation process involving various mechanisms, on the levels of expression and activity. Apart from physiological factors, several patho-physiological ones such as inflammation, infection, and stress affect CYP expression. The aim of this review is to summarize the current knowledge on the role of microtubules network in the regulation of drug metabolizing CYPs. Experiments on human and animal cell models revealed that microtubules disruption severely impaired basal and inducible expression of human CYP 1A1, 2B6, 2C8, 2C9, 2C19, and 3A4, and rat CYP 1A2, 2B1, 2B2, and 3A23. Inhibition of aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) transcriptional activity by microtubules disarray was found to be responsible for the suppressed CYP enzymes expression. However, the mechanism by which microtubules interfering agents (MIAs) inhibit GR and AhR transcriptional activities is not fully understood yet. Several lines of evidence indicate that: i) the cell cycle, G2/M phase in particular, has an influence on AhR and GR transcriptional activity, and ii) MIAs negatively modulate GR transcriptional activity via the activation of c-Jun-N-terminal kinase. In conclusion, down-regulation of major CYP enzymes by microtubules disarray is intriguing from the mechanistic point of view and in relation to the cell differentiation.

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Relationships among the cell cycle, cell proliferation, and aryl hydrocarbon receptor expression in PLHC-1 cells

Cited by 19 publications

References 62 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

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

Role of Microtubules Network in CYP Genes Expression

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