2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin receptors regulate transcription of the cytochrome P₁‐450 gene

Abstract

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dioxin, produces a diverse set of biological responses which, in some cases, reflects the altered expression of specific genes. An intracellular receptor protein binds TCDD saturably and with high affinity and mediates several of TCDD's biological effects. In mouse hepatoma cells, TCDD induces aryl hydrocarbon hydroxylase activity by activating the transcription of the cytochrome P1-450 gene. Studies of receptor-defective variant cells indicate that the activation of cytochrome P1-450 gene transcription requires functional TCDD receptors. Analysis of the DNA that flanks the 5'-end of the mouse cytochrome P1-450 gene reveals at least three control regions: a promoter, an inhibitory element, and a dioxin-responsive element (DRE). Therefore, expression of the cytochrome P1-450 gene represents a balance between negative and positive control. The DRE contains two discrete, non-overlapping DNA domains that respond to TCDD. Each TCDD-responsive domain acts independently of the other, each requires TCDD receptors for function, and each has the properties of a transcriptional enhancer. For example, the function of the DREs is relatively independent of both their location and their orientation with respect to the promoter. Together, the DREs and the TCDD-receptor complex constitute a dioxin-responsive enhancer system. Exposure of cells to TCDD results in the protection of a specific DNA domain from exonuclease digestion. This protection requires TCDD receptors. The protected domain maps to a DRE. This observation implies that the TCDD-receptor complex interacts with the DRE to activate the transcription of the cytochrome P1-450 gene.

Prenatal Exposure to TCDD Triggers Significant Modulation of microRNA Expression Profile in the Thymus That Affects Consequent Gene Expression

“…Also, CYP1A1 induction is a hallmark of AhR activation by TCDD [18], [41], [42], [43], [44]. To understand the role of TCDD-induced miRs in regulation of AhR and CYP1A1 expression, we sought to identify miRs that were up- or downregulated by TCDD in fetal thymocytes.…”

“…TCDD toxicity has been well characterized to be regulated by signaling through the AhR leading to the induction of a wide range of genes that express DREs on their promoters [20], [26], [44], [58], [59], [60], [61], [62]. However, it is not clear whether the toxic effects of TCDD may also be regulated by certain miRs.…”

SOCS2-Induced Proteasome-Dependent TRAF6 Degradation: A Common Anti-Inflammatory Pathway for Control of Innate Immune Responses

“…Following, heterodimerization of AhR and ARNT takes place at the nuclear membrane, mediating its nuclear translocation [23]. Once in the nucleus, those heterodimers are thought to bind to specific promoter sequences, termed DRE [24]. In order to evaluate whether either LXA 4 or L-kynurenine exposure initiates nuclear translocation of AhR, we performed ImageStream analysis of spleen-derived CD11c+ dendritic cells (Figure 3) after 2.5-hrs incubation in the presence of medium alone (Figure 3A), LXA 4 (Figure 3B), L-kynurenine (Figure 3C) and the prototypical AhR-ligand, FICZ (Figure 3D).…”

Dietary Indoles Suppress Delayed-Type Hypersensitivity by Inducing a Switch from Proinflammatory Th17 Cells to Anti-Inflammatory Regulatory T Cells through Regulation of MicroRNA

“…AhR is a transcription factor and belongs to bHLH-PAS family (22, 23). Activated AhR translocates to the nucleus where binding to aryl hydrocarbon receptor nuclear translocator (ARNT) generates AhR-ARNT complex that regulates genes through promoters containing a dioxin-responsive element (DRE) consensus sequence (11, 12, 24–27). AhR was characterized as a transcription factor responsible for the activation of genes encoding a number of xenobiotic metabolizing enzymes, and mediate the toxicity induced by environmental chemicals such as TCDD (28).…”