Aryl Hydrocarbon Receptor Functions as a Potent Coactivator of E2F1-Dependent Trascription Activity

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that possesses a basic-helix-loop-helix (bHLH)/Per-Arnt-Sim (PAS) domain and mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. 1,2) Unliganded AhR exists in the cytoplasm in the form of a complex with 90 kDa heat-shock protein and immunophilinrelated protein. [3][4][5][6] Upon binding to the ligand, AhR translocates to the nucleus and forms heterodimer with another bHLH/PAS protein, Ah receptor nuclear translocator (Arnt). 7)This heterodimer drives transcription from the xenobiotic responsive element (XRE) found in the promoter of xenobiotic-metabolizing enzymes, including cytochrome P450 (CYP)1A1 and CYP1A2. [8][9][10] Recent studies have shown that AhR/Arnt modulates gene expression by not only direct control of transcription but also by crosstalk with endogenous signals critical to hormone responses, cell cycle, etc.11-25) AhR/Arnt physically interacts with several effectors involved in these pathways, resulting in super activation or inhibition of the signals. Among crosstalks between AhR and signal effectors, the interactions of AhR/Arnt with estrogen receptor (ER)-a and b have been well-characterized. [11][12][13][14][15][16] ERs associate with AhR/Arnt, followed by activation of target gene transcription and estrogenic effects in the absence of estrogen. The mechanisms involve the recruitment of histone acetyltransferase (HAT) complexes such as p300 to the ER target gene. Contrary to ligand-free ER, the function of liganded ER is attenuated by AhR/Arnt. 11) Consequently, AhR plays a role as a coactivator/suppressor of other transcription factors in addition to the representative roles as a transcription factor. These multiple roles of the AhR in the regulation of gene expression may generate diverse effects of the AhR ligands.Several reports have shown constitutive activation of the AhR in the absence of an exogenous ligand, suggesting that the AhR may play an important role not only in the regulation of xenobiotic metabolism but also in the maintenance of homeostatic functions. [26][27][28] One of the possible physiological roles of the AhR is regulation of cell growth. Stable transfection of AhR cDNA into AhR-defective mouse hepatoma cells has shown that the AhR control cell-cycle progression and differentiation, and that no exogenous ligands are required for this function.29) Studies using mouse embryonic fibroblast cells (MEF) have shown that AhRϪ/Ϫ MEF proliferates more slowly than AhRϩ/ϩ MEF, presumably due to the excess production of tumor growth factor (TGF)-b in AhR null cells. 30,31) We have previously shown that overexpression of AhR, as well as AhR ligand treatment, stimulates cell proliferation of human lung cancer A549 cells.32) Activated-AhR increases the expression of several DNA synthesis regulatory factors, thus shortening the cell cycle of the late M to S phases. 32) On the other hand, Kolluri et al. have shown that AhR activation with TCD...

Deregulation of Rb-E2F1 Axis Causes Chromosomal Instability by Engaging the Transactivation Function of Cdc20–Anaphase-Promoting Complex/Cyclosome

“…Sp1 associates with E2F1 in mid-to late G 1 phase for superactivation of transcription (40). Similarly, association of various other coactivators (CBP, ANCCA, ACTR, and AhR, to name a few) with E2F1 peaks at the G 1 /S transition (40)(41)(42)(43). Unlike S-phase E2F1 targets, regulation of expression of mitotic genes by E2F1 is currently not clear.…”

Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression

“…The site-directed mutagenesis was performed by the PCR overextension method and confirmed by DNA sequencing (34). HepG2 cells were transfected with the plasmids by using a FuGENE HD (Promega) (9,33). After 24 h of incubation, the transfection medium was replaced with fresh medium containing 3MC or DMSO.…”

“…Then, this complex transactivates the target genes such as xenobiotic-metabolizing enzymes by binding to xenobiotic response element (XRE) sequences in their promoter region (4 -6). In addition to direct transcriptional regulation, AhR controls gene expressions thorough interactions with other transcription factors such as nuclear factor -light chain enhancer, estrogen receptor, and E2F (7)(8)(9).…”

Aryl Hydrocarbon Receptor Modulates NADPH Oxidase Activity via Direct Transcriptional Regulation of p40phox Expression

“…The site-directed mutagenesis was performed by the PCR overextension method and was confirmed by DNA sequencing (Xie et al, 2000). The Hepa1c1c7 cells were transfected into 48-well plates with FuGene HD (Promega) (Wada et al, 2008;Watabe et al, 2010). After 24 hours of incubation, the transfection medium was replaced with fresh medium containing 3MC or DMSO.…”