Dioxin induces transcription of fos and jun genes by ah receptor-dependent and -independent pathways

Hoffer, Amy; Chang, Ching‐yi; Puga, Alvaro

doi:10.1016/s0041-008x(96)80029-9

Cited by 118 publications

(47 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While most of TCDD-mediated biological responses are AhR-dependent, AhR-independent pathways have been suggested in recent studies (Hoffer et al, 1996;Yang and Kodavanti, 2001;Butler, et al, 2004). The ROS production and PKC-ε translocation by TCDD further support the evidence that the AhR-independent pathways may play pivotal roles in the neuronal cells.…”

Section: Discussionmentioning

confidence: 63%

Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells

Kim

Yang²

2005

Exp Mol Med

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 63%

Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells

Kim

Yang²

2005

Exp Mol Med

View full text Add to dashboard Cite

“…The induction of c-Jun and Jun-D expression by the AHR appears to result from AHR-complex binding sites in the promoters of these genes. In contrast, c-Fos induction by TCDD is dependent on a SRE motif in its promoter, and is not dependent on the presence of the AHR [Hoffer et al, 1996]. Activation of the ERK MAP kinases leads to ELK-1 phosphorylation and to binding of the ternary ELK-1/TCF complex to the SRE motif [Gille et al, 1996], potentially connecting ERK activation by TCDD to AHR-independent downstream effects on immediate-early gene expression [Tan et al, 2004]; however, neither ELK-1 phosphorylation nor formation of the ternary complex have been observed after AHR activation.…”

Section: Ahr Agonists Activate Immediate-early Response Genesmentioning

confidence: 85%

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

Marlowe

Puga

2005

J of Cellular Biochemistry

Self Cite

283

201

View full text Add to dashboard Cite

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.

show abstract

“…Comparison with the published sequence of the murine JunD promoter (de Groot et al, 1991) reveals 87% homology with the corresponding 5 0 -flanking region of the rat JunD gene, which contains three potential XREs. Puga and co-workers have shown that two isolated XREs derived from the mouse JunD promoter when cloned in front of a minimal SV40 promoter drive expression of a reporter gene (Puga et al, 1992;Hoffer et al, 1996). However, the functional relevance of these XREs in regulating the endogenous JunD promoter has not been elucidated so far.…”

Section: Loss Of Contact Inhibition By the Aryl Hydrocarbon Receptor mentioning

confidence: 99%

“…Interestingly, TCDD has been shown to increase mRNA levels of several AP-1 family members in mouse hepatoma cells (Puga et al, 1992;Hoffer et al, 1996), and more recently our own studies proved an essential Loss of contact inhibition by the aryl hydrocarbon receptor C Weiss et al role of the AhR in induction of the AP-1 transcription factor c-Jun by TCDD in rat hepatoma cells . Thus, AP-1 proteins might be involved in transcriptional activation of cyclin A.…”

mentioning

confidence: 94%

TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A

Weiss

Faust

Schreck³

et al. 2007

Oncogene

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AhR) is a transcription factor involved in physiological processes, but also mediates most, if not all, toxic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Activation of the AhR by TCDD leads to its dimerization with aryl hydrocarbon nuclear translocator (ARNT) and transcriptional activation of several phase I and II metabolizing enzymes. However, this classical signalling pathway so far failed to explain the pleiotropic hazardous effects of TCDD, such as developmental toxicity and tumour promotion. Thus, there is an urgent need to define genetic programmes orchestrated by AhR to unravel its role in physiology and toxicology. Here we show that TCDD treatment of rat liver oval cells leads to induction of the transcription factor JunD, resulting in transcriptional upregulation of the proto-oncogene cyclin A which finally triggers a release from contact inhibition. Ectopic expression of cyclin A in confluent cultures overcomes G 1 arrest, indicating that increased cyclin A levels are indeed sufficient to bypass contact inhibition. Functional interference with AhR-, but not with ARNT, abolished TCDD-induced increase in JunD and cyclin A and prevented loss of contact inhibition. In summary, we have discovered a novel AhR-dependent and probably ARNT-independent signalling pathway involving JunD and cyclin A, which mediates TCDD-induced deregulation of cell cycle control.

show abstract

Dioxin induces transcription of fos and jun genes by ah receptor-dependent and -independent pathways

Cited by 118 publications

References 67 publications

Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells

Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells

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

TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A

Contact Info

Product

Resources

About