2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits growth factor withdrawal-induced apoptosis in the human mammary epithelial cell line, MCF-10A

Davis, John W.; Melendez, Karla; Salas, Virginia M.; Lauer, Fredine T.; Burchiel, Scott W.

doi:10.1093/carcin/21.5.881

Cited by 38 publications

(26 citation statements)

References 32 publications

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“…In mammary epithelial cells, TCDD is known to trigger EGFR signaling by induction of TGF␣ mRNA and protein (26,27). Studies using HeLa cells and MEFs have shown that TCDD suppresses the checkpoint protein MAD2 or induces MAPKs in an AhRindependent manner (28,29).…”

Section: Discussionmentioning

confidence: 99%

Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling

Biswas

Srinivasan

Anandatheerthavarada

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling

Biswas

Srinivasan

Anandatheerthavarada

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…TCDD inhibits apoptosis in hepatocytes treated with UV light or 2-acetylaminofluorene, an effect that was also attributed in part to attenuation of p53 activity [Worner and Schrenk, 1996;Schrenk et al, 2004]. Apoptosis induced by growth factor withdrawal in human epithelial cells is inhibited by TCDD treatment, in correlation with activation of the EGF signaling pathway [Davis et al, 2000b]. Studies with AHR-null mice confirm the importance of the AHR in tissue homeostasis, as hepatocytes from these mice exhibit accelerated rates of apoptosis associated with increased production of TGF-b [Gonzalez and FernandezSalguero, 1998].…”

Section: Ahr-mediated Inhibition Of Apoptosismentioning

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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“…Although the role of AHR in determining apoptosis susceptibility is yet emerging (Gonzalez and Fernandez-Salguero, 1998;Reiners and Clift, 1999;Camacho et al, 2002;Park et al, 2005), much of the work in this area has been performed using conditions in which the AHR has been activated exogenously by TCDD, rather than by those that may mimic its endogenous role (Davis et al, 2000(Davis et al, , 2001Schrenk et al, 2004;Park et al, 2005). As reviewed recently by Marlowe and Puga (2005), the mechanisms by which the TCDD-activated AHR has thus far been proposed to alter apoptosis seems to involve the p53, EGFR, and/or TGF␤ signaling pathways.…”

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confidence: 99%

Lack of the Aryl Hydrocarbon Receptor Leads to Impaired Activation of AKT/Protein Kinase B and Enhanced Sensitivity to Apoptosis Induced via the Intrinsic Pathway

Wu¹,

Zhang²,

Hoagland³

et al. 2006

J Pharmacol Exp Ther

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The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is best known for its role in mediating the toxicity of many environmental contaminants such as 2,3,7,8 tetrachlorodibenzo-p-dioxin. However, the endogenous role of AHR, especially with respect to the apoptotic process, is largely unknown and contradictory. In this report, we have used a mouse hepatoma cell line (Hepa1c1c7) and its AHR-deficient derivative (LA1) to examine the effect of differing AHR levels on apoptosis susceptibility, in particular, apoptosis regulated by the intrinsic pathway. Toward this end, the cells were subjected to UV irradiation, hydrogen peroxide, and serum starvation. Analyses of a number of different endpoints of apoptosis revealed that the LA1 cells were more sensitive to these stresses than the wild-type cells, indicating that the AHR plays a cytoprotective role in the face of stimuli that initiate the intrinsic apoptotic pathway. A direct role of the AHR in mediating this effect was confirmed using both pharmacological and molecular approaches. Further analyses imply that lack of the AHR leads to an impaired survival response mediated by phosphatidylinositol 3Ј-OH kinase-Akt/protein kinase B and, to a lesser degree, epidermal growth factor receptor activation. These findings indicate that exploring the use of the AHR antagonist as agents that enhance the proapoptotic actions of cancer therapies may be a valid approach.

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits growth factor withdrawal-induced apoptosis in the human mammary epithelial cell line, MCF-10A

Cited by 38 publications

References 32 publications

Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling

Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling

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

Lack of the Aryl Hydrocarbon Receptor Leads to Impaired Activation of AKT/Protein Kinase B and Enhanced Sensitivity to Apoptosis Induced via the Intrinsic Pathway

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