Aryl hydrocarbon nuclear translocator ARNT

Fig. 5 Generic mechanism of AhR-mediated toxicity AhR mediates signal transduction by dioxin-like ligands, which form a transcription factor complex with an aryl hydrocarbon nuclear translocator protein (ARNT). This heterodimer recognizes specific DNA sequences, namely dioxin responsive elements (DREs), and leads to induction of several genes forming the so-called Ah gene battery. In this process, the elevated levels of the protein products are assumed to be involved in the toxic action of AhR ligands. AIP AhR inhibitory protein, hsp90 90-kDa heat shock protein, ARNT AhR nuclear translocator, XRE xenobiotic response element, CYPIA eyto-chrome P450 lA gene/protein (adapted from [211, 212])...

HIF3a is not well known (51). HIFl, or ARNT, the aryl-hydrocarbon nuclear translocator, belongs to the class I of bHLH-PAS proteins and was first described as binding to the aryl hydrocarbon receptor (AHR), which is also a member of class II of bHLH-PAS proteins (46). 

Klinge, C. M., Bowers, J.L., Kulakosky, P. C., Kamboj, K.K. and Swanson, H.I. (1999) The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements. 

Scheel J, Hussong R, Schrenk D, Schmitz HJ. Variability of the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene. J Hum Genet 2002 47 217-224. 

Both a and P subunits of HIF are basic helix-loop-helix PAS proteins (bHLH-PAS) (6, 7), as observed in other transcription-factor proteins (Fig. 2). The short, basic region of bHLH-PAS proteins is directly responsible for DNA binding, and the adjacent helix-loop-helix domain allows dimerization of the two HIF subunits after translocation of HIF-a to the nucleus. The PAS domain [PAS-A/PAS-B/PAC PAS PER (periodic circadian protein), aryl hydrocarbon receptor nuclear translocator (ARNT), single-minded protein (SIM) (7) PAC motif C-terminal to PAS motifs) is involved in more specific interactions between the two subunits (for review see Reference 8). It is proposed that the specific interaction between the HIF-a and HIF-P subunits promotes folding and dimerization of the bHLH region that enables subsequent DNA binding (8). HIF-a is a Class 1 bHLH-PAS protein, which means that it can homodimer-ize and heterodimerize HIF-3 (also known as ARNT, which is... 

Hirose K, Morita M, Ema M, Mimura I, Hamada H, Fujii H, Saijo Y, Gotoh O, Sogawa K, Eujii-Kuriyama Y. cDNA cloning and tissue-specific expression of a novel basic helix-loop-hehx/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt). Mol. Cell. Biol. 1996 16 1706-1713. 

Sojka, K.M. and R.S. Pollenz. Expression of aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms in juvenile and adult rainbow trout tissues. Mar. Biotechnol. 3 416-427, 2001. 

As described above, PYP is part of a family of proteins named Xanthopsins, which thus far have only been identified in proteobacteria. Nevertheless, PYP also shows striking similarities to the much larger family of PAS domains. These PAS domains were identified in proteins from all three kingdoms of fife, i.e., in the Bacteria, the Archaea, and the Eucarya. PAS is an acronym formed from the names of the proteins in which the PAS motive was first recognized the Drosophila period clock protein (PER), the vertebrate aryl hydrocarbon receptor nuclear translocator (ARNT), and the Drosophila single-minded protein (SIM). 

PHAs induce the activation of the CYPlAl and CYPIBI, via the aryl hydrocarbons receptor (AhR). This cytosolic receptor, after the aiyl hydroearbon nuclear translocator (ARNT) dimerization, enters in the nucleus and interact with genes that contain xenobiotic response element (XRE), resulting in the induction or hyper regulation of the proteins involved in the xenobiotics detoxification (Whitlock, 1999). 

Figure 5.33 Mechanism of the receptor-mediated induction of CYP1A1 by a polycyclic hydrocarbon such as TCDD. The inducer-receptor (AhR) complex enters the nucleus, binds with ARNT, and the complex binds to the CYP1A1 gene in the DNA. This induces the production of CYP1A1 mRNA, which leads to the production of CYP1A1 protein and functional enzyme. Abbreviations AIP, AhR interacting protein AhR, aryl hydrocarbon receptor HSP, heat shock protein 90 ARNT, AhR nuclear translocator E.R., endoplasmic reticulum.

Figure 32.6. Model of AhR-mediated mechanism of action of TCDD and related HAHs. TCDD binds to the AhR in the cytoplasm. This complex interacts with another cytosolic protein (ARNT) and is translocated into the nucleus where it binds to specific DNA enhancer sequences upstream of TCDD responsive genes. Exactly which genes are important in the resulting immune suppression is unclear. Abbreviations AhR, aryl hydrocarbon receptor ARNT, AhR nuclear transporter DRE, dioxin-responsive elements.

---