Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ARNT
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:150,809,713-150,876,599 (from NCBI)
Cytosolic dioxin receptor, also referred to as Ah receptor, translocates to the nucleus upon binding of ligand. Ligands include dioxin and polycyclic aromatic hydrocarbons (PAH). The complex then initiates transcription of a battery of genes involved in the activation of PAH procarcinogens. Brooks et al. (1989) studied the tissue-specific expression of the cDNA for a human gene (ARNT) required for the translocation of the ligand-bound Ah receptor into the nucleus.
The Ah receptor is involved in the induction of cytochrome P450IA1 (CYP1A1; 108330), cytochrome P450IA2 (CYP1A2; 124060), and several other enzymes that participate in xenobiotic metabolism. The 2 P450 cytochromes are important in the activation of polycyclic aromatic hydrocarbons (found in cigarette smoke and smog) and certain heterocyclic amines (found in cooked meat) to carcinogenic intermediates. The ligand-free, cytosolic form of the Ah receptor is a multimeric complex consisting of a ligand-binding subunit (AHR; 600253) and a 90-kD heat-shock protein (HSP90). Binding of ligand leads to the nuclear translocation of only the ligand-binding subunit, where it activates CYP1A1 gene transcription through interaction with specific DNA sequences termed xenobiotic responsive elements (XREs). Hoffman et al. (1991) isolated a portion of the ARNT genomic sequence by searching for human genes that complemented mouse hepatoma cells defective in nuclear translocation of the Ah receptor. Using the partial genomic fragment, they isolated an ARNT cDNA. The predicted 789-amino acid protein contains a basic helix-loop-helix (bHLH) motif, 2 regions that are similar to both the Drosophila circadian rhythm (Per) and single-minded (Sim) proteins, and a cysteine-rich region. ARNT is required for Ah receptor function. By Northern blot analysis, ARNT is expressed in liver as low abundance 2.6- and 4.2-kb mRNAs. The authors isolated an additional ARNT cDNA lacking a 45-nucleotide segment, suggesting that ARNT transcripts are alternatively spliced.
Reisz-Porszasz et al. (1994) cloned a cDNA encoding the mouse homolog of ARNT. The predicted 791-amino acid protein is 94% identical to human ARNT. The authors noted that the region showing homology to the Drosophila Per and Sim proteins is called the PAS domain and contains 2 copies of an approximately 50-amino acid direct repeat. The PAS domains of Per and Sim mediate heterodimerization between these 2 proteins.
Using an electrophoretic mobility shift assay and antibodies against ARNT, Reyes et al. (1992) showed that ARNT is a structural component of the XRE-binding form of the Ah receptor. They found that the 176-kD nuclear form of the Ah receptor is a heterodimer consisting of the ligand-binding subunit (AHR) and the 87-kD ARNT. The authors suggested that the bHLH motif of ARNT is responsible for its interacting with both the XRE and the ligand-binding subunit.
Hypoxia-inducible factor-1 (HIF1) is a transcription factor found in mammalian cells cultured under reduced oxygen tension that plays an essential role in cellular and systemic homeostatic responses to hypoxia. HIF1 is a heterodimer composed of a 120-kD HIF1-alpha subunit (603348) complexed with a 91- to 94-kD HIF1-beta subunit. Wang et al. (1995) determined that HIF1-beta is identical to ARNT. Hogenesch et al. (1997) found that AHR, HIF1-alpha, and MOP2 (603349) have different expression profiles, but all share ARNT as a common dimeric partner.
Reisz-Porszasz et al. (1994) reported that mouse Arnt cannot form homodimers but can heterodimerize efficiently with mouse Ahr in vitro. Studies of Arnt deletion mutants showed that both the bHLH and PAS domains are required for maximal heterodimerization. An Arnt protein containing just the bHLH and PAS domains is only moderately reduced in its ability to complement Arnt-deficient mutant cells.
A heterodimer of AHR and ARNT, which are basic helix-loop-helix/PAS family transcription factors, mediates most of the toxic effects of dioxins. Ohtake et al. (2003) demonstrated that the agonist-activated AHR/ARNT heterodimer directly associates with the estrogen receptors ER-alpha (133430) and ER-beta (601663). They showed that this association results in the recruitment of unliganded estrogen receptor and the coactivator p300 (602700) to estrogen-responsive gene promoters, leading to activation of transcription and estrogenic effects. The function of liganded estrogen receptor was found to be attenuated. Estrogenic actions of AHR agonists were detected in wildtype ovariectomized mouse uteri, but were absent in Ahr -/- or Er-alpha -/- ovariectomized mice. Ohtake et al. (2003) concluded that their findings suggest a novel mechanism by which estrogen receptor-mediated estrogen signaling is modulated by a coregulatory-like function of activated AHR/ARNT, giving rise to adverse estrogen-related actions of dioxin-type environmental contaminants.
To gain insight into the mechanism of CD30 (153243) signaling in anaplastic large cell lymphoma and Hodgkin lymphoma, Wright and Duckett (2009) used an affinity purification strategy that led to the identification of ARNT as a CD30-interacting protein that modulates the activity of the RelB subunit (604758) of the transcription factor nuclear factor kappa-B (NFKB; see 164011). Anaplastic large-cell lymphoma cells that were deficient in ARNT exhibited defects in RelB recruitment to NFKB-responsive promoters, whereas RelA (164014) recruitment to the same sites was potentiated, resulting in the augmented expression of these NF-kappa-B-responsive genes. Wright and Duckett (2009) concluded that ARNT functions in concert with RelB in a CD30-induced negative feedback mechanism.
Crystal Structure
Wu et al. (2015) described the crystal structure for each of mouse Hif2-alpha (603349)-Arnt and Hif1-alpha (603348)-Arnt heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by Hif2-alpha-Arnt and Hif1-alpha-Arnt, wherein Arnt spirals around the outside of each Hif-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends, and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.
Scheel and Schrenk (2000) determined that the ARNT gene contains 22 exons, varying in size from 25 to 214 bp, and spans 65 kb. Splice junctions follow the GT/AG consensus except for intron 11 starting with GC at its 5-prime end.
By the study of somatic cell hybrids, Brooks et al. (1989) localized the ARNT gene to 1pter-q12 and mapped the murine homolog to chromosome 3. Johnson et al. (1993) localized the ARNT gene to 1q21 by study of DNA from mouse/human hybrid clones that retained translocations involving human chromosome 1, by segregation analysis in 9 informative CEPH families, and by in situ hybridization. They mapped the mouse homolog to chromosome 3 using a panel of 16 hamster/mouse somatic cell hybrids and regionally mapped it on chromosome 3 by linkage analysis in an interspecific backcross.
The TEL/ETV6 gene (600618) is located at 12p13 and encodes a member of the ETS family of transcription factors. TEL is frequently involved in chromosomal translocations in human malignancies, usually resulting in the expression of fusion proteins between the amino-terminal part of TEL and either unrelated transcription factors or protein tyrosine kinases. Salomon-Nguyen et al. (2000) characterized a t(1;12)(q21;p13) translocation observed in a case of acute myeloblastic leukemia (AML-M2). At the protein level, the untranslocated TEL copy and, as a result of the t(1;12) translocation, a fusion protein between TEL and essentially all of the ARNT gene, were expressed. The involvement of ARNT in human leukemogenesis had not previously been described.
Studying the etiology of nonsyndromic oral clefts (OFC1; 119530), Kayano et al. (2004) assessed whether there is any association in the Japanese population of such clefts with SNPs in the AHR, CYP1A1, or ARNT genes using the transmission disequilibrium test (TDT) and a case-control study. The products of these 3 genes are all involved in the metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is suspect because when administered during organogenesis in mice, a high incidence of cleft palate results in fetuses. Kayano et al. (2004) found no evidence of involvement of AHR or CYP1A1 with clefting; however, specific SNPs in ARNT were associated with nonsyndromic clefting in the Japanese population studied. When a haplotype consisting of 567G/C and IVS12-19T/G in ARNT was considered, preferential transmission of the CT haplotype was observed (p = 0.0012). In the case-control study, a significant association of IVS12-19T/G was observed (p = 0.021).
Brooks, B., Johnson, B., Heinzmann, C., Mohandas, T., Sparkes, R., Jones, S., Bennett, P., Balacs, T., Moore, G., Conley, L., Hankinson, O. Localization of a gene required for the nuclear translocation of the dioxin receptor to human chromosome 1 and mouse chromosome 3 and a human RFLP with MspI. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A132 only, 1989.
Hoffman, E. C., Reyes, H., Chu, F.-F., Sander, F., Conley, L. H., Brooks, B. A., Hankinson, O. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252: 954-958, 1991. [PubMed: 1852076] [Full Text: https://doi.org/10.1126/science.1852076]
Hogenesch, J. B., Chan, W. K., Jackiw, V. H., Brown, R. C., Gu, Y.-Z., Pray-Grant, M., Perdew, G. H., Bradfield, C. A. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J. Biol. Chem. 272: 8581-8593, 1997. [PubMed: 9079689] [Full Text: https://doi.org/10.1074/jbc.272.13.8581]
Johnson, B., Brooks, B. A., Heinzmann, C., Diep, A., Mohandas, T., Sparkes, R. S., Reyes, H., Hoffman, E., Lange, E., Gatti, R. A., Xia, Y.-R., Lusis, A. J., Hankinson, O. The Ah receptor nuclear translocator gene (ARNT) is located on q21 of human chromosome 1 and on mouse chromosome 3 near Cf-3. Genomics 17: 592-598, 1993. [PubMed: 8244375] [Full Text: https://doi.org/10.1006/geno.1993.1377]
Kayano, S., Suzuki, Y., Kanno, K., Aoki, Y., Kure, S., Yamada, A., Matsubara, Y. Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT). Am. J. Med. Genet. 130A: 40-44, 2004. [PubMed: 15368494] [Full Text: https://doi.org/10.1002/ajmg.a.30023]
Ohtake, F., Takeyama, K., Matsumoto, T., Kitagawa, H., Yamamoto, Y., Nohara, K., Tohyama, C., Krust, A., Mimura, J., Chambon, P., Yanagisawa, J., Fujii-Kuriyama, Y., Kato, S. Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423: 545-550, 2003. [PubMed: 12774124] [Full Text: https://doi.org/10.1038/nature01606]
Reisz-Porszasz, S., Probst, M. R., Fukunaga, B. N., Hankinson, O. Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT). Molec. Cell. Biol. 14: 6075-6086, 1994. [PubMed: 8065341] [Full Text: https://doi.org/10.1128/mcb.14.9.6075-6086.1994]
Reyes, H., Reisz-Porszasz, S., Hankinson, O. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science 256: 1193-1195, 1992. [PubMed: 1317062] [Full Text: https://doi.org/10.1126/science.256.5060.1193]
Salomon-Nguyen, F., Della-Valle, V., Mauchauffe, M., Busson-Le Coniat, M., Ghysdael, J., Berger, R., Bernard, O. A. The t(1;12)(q21;p13) translocation of human acute myeloblastic leukemia results in a TEL-ARNT fusion. Proc. Nat. Acad. Sci. 97: 6757-6762, 2000. [PubMed: 10829078] [Full Text: https://doi.org/10.1073/pnas.120162297]
Scheel, J., Schrenk, D. Genomic structure of the human Ah receptor nuclear translocator gene (hARNT). Hum. Genet. 107: 397-399, 2000. [PubMed: 11129342] [Full Text: https://doi.org/10.1007/s004390000379]
Wang, G. L., Jiang, B.-H., Rue, E. A., Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O(2) tension. Proc. Nat. Acad. Sci. 92: 5510-5514, 1995. [PubMed: 7539918] [Full Text: https://doi.org/10.1073/pnas.92.12.5510]
Wright, C. W., Duckett, C. S. The aryl hydrocarbon nuclear translocator alters CD30-mediated NF-kappa-B-dependent transcription. Science 323: 251-255, 2009. [PubMed: 19131627] [Full Text: https://doi.org/10.1126/science.1162818]
Wu, D., Potluri, N., Lu, J., Kim, Y., Rastinejad, F. Structural integration in hypoxia-inducible factors. Nature 524: 303-308, 2015. [PubMed: 26245371] [Full Text: https://doi.org/10.1038/nature14883]