Ah receptor ligands and tumor promotion: survival of neoplastic cells

Schwarz, Michael; Buchmann, Albrecht; Stinchcombe, Stefan; Kalkuhl, Arno; Bock, K. W.

doi:10.1016/s0378-4274(99)00247-7

Cited by 63 publications

(30 citation statements)

References 45 publications

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“…The carcinogenic effect of polyaromatic hydrocarbons has been discussed in terms of Ah receptor-mediated induction of xenobiotic enzymes of the P450 system with subsequent production of active carcinogenic epoxides. [21] A number of agonists of the Ah receptor either act as direct tumour promoters [23] or play a role in the selection of malignant cells by preferential apoptosis of normal cells. [24] In contrast, agonists of the Ah receptor inducing apoptosis in malignant cells have been discussed as possible therapeutic agents for selective induction of cell death in malignant cells.…”

Section: Discussionmentioning

confidence: 99%

Malassezin, a Novel Agonist of the Aryl Hydrocarbon Receptor from the Yeast Malassezia furfur, Induces Apoptosis in Primary Human Melanocytes

et al. 2005

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Pityriasis versicolor is the most common skin mycosis in humans worldwide. Yeasts of the genus Malassezia, particularly M. furfur, a saprophyte occurring widely on human skin, are generally regarded as the causative agents. Pityriasis versicolor is often accompanied by a long-lasting depigmentation that persists even after successful antimycotic therapy. M. furfur is able to convert tryptophan into a variety of indole alkaloids, some of them showing biological properties that correlate well with certain clinical features of pityriasis versicolor. This suggests a possible role for these compounds in the depigmentation process. We now report that human melanocytes undergo apoptosis when exposed to the crude mixture of tryptophan metabolites from M. furfur. The active compound was identified as malassezin, previously isolated by us from the same source and characterized as an agonist of the aryl hydrocarbon (Ah) receptor. The compound could, therefore, contribute to the marked depigmentation observed during the course of pityriasis versicolor.

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Section: Discussionmentioning

confidence: 99%

Malassezin, a Novel Agonist of the Aryl Hydrocarbon Receptor from the Yeast Malassezia furfur, Induces Apoptosis in Primary Human Melanocytes

et al. 2005

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“…Furthermore, AHR activation by TCDD blocks UV irradiation-induced apoptosis (Worner and Schrenk, 1996;Schrenk et al, 2004). The capacity of various Ah receptor ligands to act as tumor promoters has been attributed to their ability to inhibit the apoptotic elimination of initiated cells bearing genotoxic lesions (Schwarz et al, 2000). Our data suggest that they may do so by activating the AHR and inhibiting apoptosis through repression of E2F1 proapoptotic target genes, thus preventing the elimination of cells that have lost normal cell cycle control and promoting their proliferation.…”

Section: Ahr-e2f1 Interaction Inhibits Apoptosismentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis

Marlowe

Fan

Chang

et al. 2008

MBoC

113

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Cellular stress by DNA damage induces checkpoint kinase-2 (CHK2)-mediated phosphorylation and stabilization of the E2F1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic E2F1 target genes, including Apaf1 and p73. This report characterizes an interaction between the aryl hydrocarbon (Ah) receptor (AHR), a ligand-activated transcription factor, and E2F1 that results in the attenuation of E2F1-mediated apoptosis. In Ahr ؊/؊ fibroblasts stably transfected with a doxycycline-regulated AHR expression vector, inhibition of AHR expression causes a significant elevation of oxidative stress, ␥H2A.X histone phosphorylation, and E2F1-dependent apoptosis, which can be blocked by small interfering RNA-mediated knockdown of E2F1 expression. In contrast, ligand-dependent AHR activation protects these cells from etoposide-induced cell death. In cells expressing both proteins, AHR and E2F1 interact independently of the retinoblastoma protein (RB), because AHR and E2F1 coimmunoprecipitate from extracts of RBnegative cells. Additionally, chromatin immunoprecipitation assays indicate that AHR and E2F1 bind to the Apaf1 promoter at a region containing a consensus E2F1 binding site but no AHR binding sites. AHR activation represses Apaf1 and TAp73 mRNA induction by a constitutively active CHK2 expression vector. Furthermore, AHR overexpression blocks the transcriptional induction of Apaf1 and p73 and the accumulation of sub-G 0 /G 1 cells resulting from ectopic overexpression of E2F1. These results point to a proproliferative, antiapoptotic function of the Ah receptor that likely plays a role in tumor progression. INTRODUCTIONMembers of the E2F family of transcription factors are critical regulators of the G 1 /S phase transition of the cell cycle, during which their transcriptional activity is generally controlled through interaction with retinoblastoma (RB) family proteins. In addition, E2F proteins have functions beyond the G 1 /S phase transition that impact cell proliferation in a variety of ways (Dimova and Dyson, 2005). The E2F family consists of six extensively characterized and three less wellstudied members. E2F1, -2, and -3a are potent activators of transcription, bind exclusively to RB-p105, and are cyclically expressed during the cell cycle. E2F3b and -4, which can interact with RB-p107 and -p130, and E2F5, which binds only to p130, are poor transcriptional activators, and they function mainly as repressors through their recruitment of RB proteins to E2F-regulated promoters (Dyson, 1998;Nevins, 1998;DeGregori and Johnson, 2006). In general, the E2Fs with transactivator activity promote cell cycle progression, whereas the E2Fs with transrepressor activity function in cell cycle exit and differentiation (Dimova and Dyson, 2005). E2F6-8 are distinct from the other E2F members, lacking the transactivation and RB-binding domains, and they repress transcription in an RB-independent manner (Frolov and Dyson, 2004;DeGregori and Johnson, 2006).The best-characterized function of E2F ...

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“…The overall effect of TCDD in this system is thus to accelerate the rate at which DNA-damaged cells convert to a neoplastic phenotype [Luebeck et al, 2000]. Stimulation of cell division in these assays is negligible [Buchmann et al, 1994], hence, the primary effect of TCDD is the inhibition of apoptosis, which has also been shown to occur in Myc transgenic mice [Buchmann et al, 1994;Schwarz et al, 2000] and in the promotion of ovarian tumors in rats [Davis et al, 2000a]. Absence of tumor promotion by TCDD treatment in rat strains lacking a functional AHR suggests that the Ah receptor is required for this effect, which has been shown to include activation of MDM2 and attenuation of p53 probably by increased ubiquitination [Viluksela et al, 2000;Paajarvi et al, 2005].…”

Section: Ahr-mediated Inhibition Of Apoptosismentioning

confidence: 99%

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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Ah receptor ligands and tumor promotion: survival of neoplastic cells

Cited by 63 publications

References 45 publications

Malassezin, a Novel Agonist of the Aryl Hydrocarbon Receptor from the Yeast Malassezia furfur, Induces Apoptosis in Primary Human Melanocytes

Malassezin, a Novel Agonist of the Aryl Hydrocarbon Receptor from the Yeast Malassezia furfur, Induces Apoptosis in Primary Human Melanocytes

The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis

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

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