Why Does ARNT2 Behave Differently from ARNT?

Abstract

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a member of the bHLH PAS (basic helix-loop-helix Period/ARNT/Single-minded) family of transcription factors. It is the obligatory dimerization partner for many other members of this family, including the aryl hydrocarbon receptor (AHR) and hypoxia-inducible factors 1α and 2α (HIF-1/2α). Agonists for AHR include a variety of environmentally important toxicants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and polycyclic aromatic hydrocarbons (PAHs) such as 3-methylcholanthrene (3MC) and benzo[a]pyrene (BAP). The mechanism of transcriptional activation by AHR is best understood for the CYP1A1 gene. After binding ligand, AHR translocates into the nucleus and dimerizes with ARNT. The AHR/ARNT heterodimer then binds to specific regulatory sequences, termed xenobiotic response elements (XREs), in the enhancer regions of CYP1A1 (and other responsive genes). Transcriptional coactivators the associated with the AHR/ARNT dimer as it resides on the enhancer region. These coactivators in turn direct the recruitment of RNA polymerase II (pol II) and the other general transcription factors to the promoter regions of genes, resulting in the initiation of transcription of those genes. Transcriptional activation of genes (as yet not fully defined) in this fashion is believed to underlie many of the toxic effects of TCDD, including its potent carcinogenicity. Metabolism of PAHs by CYP1A1 and other enzymes that are upregulated via AHR/ARNT critically impact the carcinogenic activities of these compounds. HIF-1/2α activity is regulated not via a small molecule ligand, but indirectly, via oxygen tension. Briefly, HIF-1/2α is proteolytically degraded very rapidly under normoxic conditions. Under reduced oxygen conditions, it is stabilized, translocates into the nucleus, and dimerizes with ARNT. The HIF-1/2α/ARNT heterodimer then binds hypoxia response elements in responsive genes, thereby activating these genes in a manner similar to that described above for AHR/ARNT. HIF-1/2 represents the "master regulator" of the hypoxic response, modulating the expression of a variety of genes important in a number of pathological conditions including cancer, heart disease, cerebrovascular disease, and chronic obstructive pulmonary disease. ARNT is therefore an essential participant in the physiologic response to two important environmental insults: chemical toxicants and hypoxia. ARNT also participates in several developmental pathways via dimerization with other partner proteins not discussed above. The domain structure of ARNT is shown in Figure 1. The bHLH motif is located within its amino-terminal region. Further toward the carboxy-terminus is the PAS region, which contains two approximately fifty amino acid degenerate repeat segments, PAS-A and PAS-B. Dimerization of ARNT with AHR and with HIF-1α requires both the HLH and PAS regions. The basic region contacts DNA, although there is some evidence that part of the PAS region