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ahr

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Official Full Name
aryl hydrocarbon receptor
Background
This gene encodes a ligand-activated transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. This receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450. Its ligands included a variety of aromatic hydrocarbons.
Synonyms
AHR; aryl hydrocarbon receptor; bHLHe76; AH-receptor; ah receptor; aromatic hydrocarbon receptor; class E basic helix-loop-helix protein 76

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor belonging to a member of the subfamily of the basic helix-loop-helix (bHLH) superfamily PAS (periodicity/aryl hydrocarbon receptor nuclear translacator/single-minded) (bHLH-PAS). The AHR molecule can be divided into three functional domains: the PAS region, the b-helix-loop-helix region (bHLH), and the transcriptional activation region (HLH). The primary role of the PAS region is to increase the stability of heterodimer formation between AHR and the aromatic hydrocarbon receptor nuclear transcription factor (ARNT). It also participates in the binding of ligands and causes the release of heat shock protein 90 (HSP90). The bHLH structure at the N-terminus determines the dimerization of protein molecules and their binding to DNA. The b region determines the specificity of binding to the DNA sequence, while the HLH region is the interface for protein dimerization. HLH primarily mediates transcriptional activation of downstream genes by AHR.

Aromatic hydrocarbons act as ligand-activated transcription factors, and there are two types of ligands that activate AHR, exogenous and endogenous ligands. Exogenous ligands are mainly compounds such as halogenated aromatic hydrocarbons (HAHs), which are mostly contaminants produced in industrial processes. Among them, TCDDs are the most exogenous ligands that are currently found to bind to AHR and are the most studied compounds. It mainly promotes the expression of the metabolic enzyme cytochrome p450-1 (CYP1A1, CYP1A2, CYP1B1) by activating the AHR signaling pathway, resulting in epoxide-induced DNA damage and carcinogenesis. Endogenous ligands include anthraquinones, tetrapyrroles, etc., which are products of physiological metabolic processes in vivo.

Aromatic hydrocarbon receptors participate in the development of tumors mainly by promoting cell proliferation and inhibiting apoptosis by binding to ligands. In addition, clinical studies have shown that AHR is highly expressed in tissues such as breast cancer, endometrial cancer, prostate cancer, lung cancer, gastric cancer, liver cancer, and colon cancer. And AHR is associated with the degree of malignancy of cancer.

AHR Signaling Pathway

Under normal conditions, AHR forms a complex with HSP, p23 protein, and c-Src (cell-Sarcoma, non-receptor tyrosine kinase) protein kinase in the cytoplasm. When ligands appear, AHR can be activated by ligands via two pathways. One is that the classical signaling pathway is the XRE-regulated DNA-binding pathway, and the other is the non-classical signaling pathway without XRE regulation. Both pathways lead to changes in the expression levels of downstream CYP1A1 and other genes, which promote tumorigenesis. The classical signaling pathway is that after the appearance of the ligand, AHR immediately undergoes conformational change with the ligand and translocates into the nucleus, and then AHR is heterodimerized with the aryl hydrocarbon receptor nuclear translocator (ARNT). The reaction forms an AHR/ARNT aryl hydrocarbon receptor complex (AHRC). The activated AHRC can also act as a transcription factor complex to bind to the XRE upstream of the target gene promoter, resulting in transcription and expression of downstream target genes, resulting in a series of corresponding biological effects.

Esser et al. have confirmed that the non-canonical signaling pathway of AHR is mainly reflected in the following aspects: 1. Changing the survival and proliferation of cells by affecting physiological processes such as cell cycle, apoptosis, and cell-contact inhibition interaction; 2. The interaction between the inflammation-related transcription factor nuclear factor-kappa B (NF-κB) and AHR promotes AHR signaling and induces expression of CYP1A1; 3. aryl hydrocarbon receptor-estrogen receptor (AHR-ER) signaling pathway.

Figure 1. Aryl Hydrocarbon Receptor (AHR) signaling pathway. Red: upregulated gene expression after AHR activation, green: downregulated gene expression after AHR activation. (Becker, et al. 2016).

AHR Regulates the Cell Cycle

AHR can induce the expression of some genes such as c-myc and c-Jun under the activation of ligands so that cells can enter the cell cycle from the G0 phase and promote tumor cell proliferation. Yin et al. found that in the mouse hepatoma cell (Hepa1) experiment, AHR was inhibited after the addition of the ligand TCDD inhibitor, and P27 was significantly increased in hepatoma cells (a thermostable protein with a relative molecular mass of 27,000, which can inhibit the cell cycle). Protein CDKs, CDKs promote cell entry into S phase). The proportion of G0/G1 phase of liver cancer cell cycle decreased from 83% to 39%. The increase of P27 inhibited CDKs and arrested cells in G1 phase. This result indicates that the cell cycle is arrested after AHR is inhibited.

In the study of rat hepatoma cells, tumor necrosis factor (TNF-α) itself has no effect on cell proliferation. However, when the exogenous ligand TCDD of AHR and TNF-α are added together to rat liver WB-F344 cells, AHR is activated, the percentage of cells entering the S phase and the number of cells both increase. Cyclin mRNA and protein levels also increase. The above results indicate that AHR is involved in cell proliferation, and ligand-activated AHR can accelerate cell proliferation by regulating cell cycle.

AHR and Tumor Cell Apoptosis and Invasion

Tumor cell growth and apoptosis have a certain relationship with aromatic hydrocarbon receptors. Apoptosis is an important physiological way for the body to prevent the development of tumor cells, and the widely accepted tumor-promoting mechanism is to inhibit the apoptosis of tumor cells. The researchers found that in three different lymphoma cell lines, the expression of cyclooxygenase-2 (COX-2) was increased after activation of AHR with TCDD, and the expression of apoptosis-related genes Bcl-xl and Mcl-1 were regulated. Then leads to the loss of programmed cell death in tumor cells and accelerates the progression of lymphoma in vivo.

In a study by Yin et al., gastric cancer cells (MKN45, SGC7901) were transfected with AHR siRNA (small interfering RNA), and MKN45 transfected with AHR siRNA was found compared with gastric cancer cells transfected with siRNA. The mRNA and protein levels of AHR in SGC7901 cells were significantly reduced, suggesting that AHR siRNA successfully inhibited AHR expression. AHR siRNA was also used to transfect SGC7901 cells for tumor cell migration and invasion (Transwell) assays. The results showed that the number of migrated cells in the experimental group (60. 89 ± 5.78) was significantly lower than that in the control group (118.43 ± 7.83, P < 0.05). In addition, it was found that the invasive activity of SGC7901 cells transfected with AHR siRNA was reduced compared to siRNA-transfected cell invasive activity (75. 14 ± 8. 684) (30.11 ± 4. 865, P < 0.05). Taken together, these results indicate that the migration and invasion of SGC7901 cells are inhibited after inhibition of AHR.

References:

  1. Ronnekleivkelly, S. M., Nukaya, M., Díazdíaz, C. J., Megna, B. W., Carney, P. R., & Geiger, P. G., et al. (2016). Aryl hydrocarbon receptor-dependent apoptotic cell death induced by the flavonoid chrysin in human colorectal cancer cells. Cancer Letters, 370(1), 91-99.
  2. Esser, C., & Rannug, A. (2015). The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacological Reviews, 67(2), 259.
  3. Powell, J. B., & Ghotbaddini, M. (2014). Cancer-promoting and inhibiting effects of dietary compounds: role of the aryl hydrocarbon receptor (ahr). Biochemistry & Pharmacology Open Access, 3(1).
  4. Yin, J., Sheng, B., Qiu, Y., Yang, K., Xiao, W., & Yang, H. (2016). Role of ahr in positive regulation of cell proliferation and survival. Cell Proliferation, 49(5), 554-560.
  5. Yin, X. F., Chen, J., Mao, W., Wang, Y. H., & Chen, M. H. (2013). Downregulation of aryl hydrocarbon receptor expression decreases gastric cancer cell growth and invasion. Oncology Reports, 30(1), 364-370.
  6. Becker, A., Klapczynski, A., Kuch, N., Arpino, F., Simonkeller, K., & De, L. T. C., et al. (2016). Gene expression profiling reveals aryl hydrocarbon receptor as a possible target for photobiomodulation when using blue light. Scientific Reports, 6, 33847.