Ah responsive elements

Few polymorphisms have been detected in the human AHR gene. Thus far only one human AHR polymorphism has been shown to exert a substantial effect on receptor function human AHR that encodes serine at codon 517, when in combination with isoleucine at 570 and lysine at 554 (a presumed haplotype found only in individuals of African descent), fails to sustain CYP1A1 induction in vitro even though this variant is competent to bind the inducer, TCDD, and to bind AH response elements derived from the CYP1A1 gene (80). 

The AHR must dimerize with ARNT in order to bind to AH response elements and alter gene transcription. Several polymorphic sites have been identified in the human ARNT gene but none of these appears to affect CYP1A2 activities in vivo as judged by caffeine phenotyping (102). 

AHRE AH response element (also known as DRE = dioxin... 

The H2 receptor is the second class of HA receptors. This is another G-protein-coupled receptor but, unlike the Hi receptor, the H2 receptor is coupled to adenylyl cyclase via the GTP-binding Gs protein (Hill et ah, 1997). Encoded by an intronless gene and located on human chromosome 5, the H2 receptor is made up of c. 358 amino acids (Gantz et ah, 1991 Traiffort et ah, 1995). Activation of the H2 receptor causes an accumulation of cAMP and activation of protein kinase A that eventually leads to the activation of cyclic-AMP-response element (CRE)-binding protein (CREB) (Hill et ah, 1997). In neurons, the H2 receptor mediates its excitatory effects by blocking the Ca2+-dependent K+ channel (Haas Konnerth, 1983). 

Yueh, M.F., Huang, Y.H., Hiller, A., Chen, S., Nguyen, N. and Tukey, R.H. (2003) Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. Journal of Biological Chemistry, 278, 15001-15006. 

Figure 9.9 Interaction of the Ah-receptor-ligand complex with the 5 flanking region of the P450 1A1 gene. Two dioxin responsive elements (DREs) appear to lie approximately 1000 or more base pairs upstream from the 1A1 transcriptional s tart site. These elements appear to be transcriptional enhancers, whereas less direct evidence indicates an inhibitory element ( negative control element ) between 400 and 800 bases upstream. The negative control element may inhibit the 1A1 promoted although the conditions for this inhibition are, as yet, undefined. (Adapted from A. B. Okey, Pharmacol. Ther. 45 241-298, 1990.)...

Fig. 5.1 Principle behind the CALUX bioassay for Ah-receptor agonists. Following binding of the agonist to the Ah-receptor, the complex will be transported to the nucleus and bind to a so-called dioxin responsive element, resulting in the increased transcription of the luciferase gene and production of luciferase. Following incubation this enzyme can subsequently be measured in cell lysates by a light producing reaction.

Lee, J.M., Hanson, .M., et ah, Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant-responsive element in IMR-32 human neuroblastoma cells, J. Biol. Chem., 276, 20011-20016, 2001. 

Iron response elements consist of short stretches of ribonucleic acid, and they occur in the mRNA coding for ferritin, transferrin receptor, and 8-aminolevulinic acid s)mthase. Each IRE can be bound by an IRP. Several different IRPs exist. Surprisingly, one of the IREs is quite similar to aconitase, the Krebs cycle enzyme (Kim et ah, 1996 Toth and Bridges, 1995 Henderson et ah, 1996). All IRPs contain an iron binding site. This site consists of several residues of cysteine. To be more specific, the sulfhydryl groups of cysteine residues function to bind iron atoms. 

---