Aryl hydrocarbon receptor gene

The Aryl hydrocarbon receptor (AHR) is a gene that encodes a protein of the same name, which is a ligand-activated transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. The AHR is a member of the basic helix-loop-helix (bHLH) family of transcription factors and plays a crucial role in the metabolism of xenobiotics.

Structure

The AHR gene is located on chromosome 7 at the 7p21.1 locus. It spans approximately 54 kilobases and consists of 11 exons. The protein encoded by the AHR gene is composed of 848 amino acids and contains several functional domains, including a basic helix-loop-helix (bHLH) domain, a PAS domain, and a transactivation domain.

bHLH Domain

The bHLH domain is responsible for DNA binding and dimerization with other proteins. This domain is crucial for the receptor's ability to regulate gene expression by binding to specific DNA sequences known as xenobiotic response elements (XREs).

PAS Domain

The PAS domain is involved in ligand binding and protein-protein interactions. It is named after the first three proteins in which it was identified: Period (PER), AHR nuclear translocator (ARNT), and Single-minded (SIM).

Transactivation Domain

The transactivation domain is located at the C-terminal end of the protein and is responsible for activating transcription of target genes.

Function

The primary function of the AHR is to mediate the effects of environmental toxins, such as dioxins and polycyclic aromatic hydrocarbons (PAHs). Upon binding to these ligands, the AHR translocates to the nucleus, where it dimerizes with the AHR nuclear translocator (ARNT). This complex then binds to XREs in the promoter regions of target genes, leading to their transcriptional activation.

Role in Xenobiotic Metabolism

AHR plays a pivotal role in the metabolism of xenobiotics by regulating the expression of cytochrome P450 enzymes, such as CYP1A1, CYP1A2, and CYP1B1. These enzymes are involved in the oxidative metabolism of a wide range of environmental chemicals, facilitating their detoxification and excretion.

Developmental and Physiological Roles

Beyond its role in xenobiotic metabolism, AHR is also involved in various developmental and physiological processes. It has been implicated in the regulation of immune system function, cell cycle control, and cell differentiation.

Clinical Significance

Mutations or polymorphisms in the AHR gene can affect an individual's susceptibility to environmental toxins and influence the risk of developing certain diseases. For example, variations in AHR expression or function have been associated with increased risk of cancer, autoimmune diseases, and cardiovascular diseases.

Cancer

AHR has been studied extensively in the context of cancer, as its activation can lead to the expression of genes involved in cell proliferation and survival. Aberrant AHR signaling has been linked to the development of various cancers, including lung cancer, breast cancer, and liver cancer.

Autoimmune Diseases

AHR is involved in the regulation of immune responses, and dysregulation of AHR signaling has been associated with autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis.

Cardiovascular Diseases

Research suggests that AHR may play a role in the development of cardiovascular diseases by influencing the expression of genes involved in inflammation and lipid metabolism.

Research Directions

Ongoing research is focused on understanding the diverse roles of AHR in health and disease, as well as its potential as a therapeutic target. Studies are exploring the development of AHR modulators that could be used to treat diseases associated with its dysregulation.

See Also

• Transcription factor
• Xenobiotic
• Cytochrome P450
• Dioxin

External Links

• AHR Gene - NCBI
• AHR Gene - GeneCards