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Event: 944
Key Event Title
dimerization, AHR/ARNT
Short name
Biological Context
Level of Biological Organization |
---|
Molecular |
Cell term
Cell term |
---|
eukaryotic cell |
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
protein dimerization activity | aryl hydrocarbon receptor | increased |
protein dimerization activity | aryl hydrocarbon receptor nuclear translocator | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
AHR activation to ELS mortality, via VEGF | KeyEvent | Amani Farhat (send email) | Open for citation & comment | WPHA/WNT Endorsed |
AhR mediated mortality, via COX-2 | KeyEvent | Markus Hecker (send email) | Open for citation & comment | WPHA/WNT Endorsed |
AHR mediated epigenetic reproductive failure | KeyEvent | Jon Doering (send email) | Under development: Not open for comment. Do not cite | |
AhR activation leading to preeclampsia | KeyEvent | Sabrina Tait (send email) | Under development: Not open for comment. Do not cite | Under Development |
Ahr mediated early stage mortality via craniofacial malformations | KeyEvent | Prarthana Shankar (send email) | Under development: Not open for comment. Do not cite | Under Review |
Ahr mediated early stage mortality via cardiovascular toxicity | KeyEvent | Prarthana Shankar (send email) | Under development: Not open for comment. Do not cite | Under Review |
AhR activation leading to Premature ovarian insufficiency | KeyEvent | Sapana Kushwaha (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
chicken | Gallus gallus | High | NCBI |
zebrafish | Danio rerio | High | NCBI |
mouse | Mus musculus | High | NCBI |
Coturnix japonica | Coturnix japonica | High | NCBI |
Phasianus colchicus | Phasianus colchicus | High | NCBI |
rainbow trout | Oncorhynchus mykiss | High | NCBI |
Pagrus major | Pagrus major | High | NCBI |
Acipenser fulvescens | Acipenser fulvescens | High | NCBI |
Acipenser transmontanus | Acipenser transmontanus | High | NCBI |
Salmo salar | Salmo salar | High | NCBI |
Xenopus laevis | Xenopus laevis | High | NCBI |
human | Homo sapiens | High | NCBI |
Ambystoma mexicanum | Ambystoma mexicanum | High | NCBI |
Microgadus tomcod | Microgadus tomcod | High | NCBI |
Life Stages
Life stage | Evidence |
---|---|
Embryo | High |
Development | High |
All life stages | High |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | High |
Key Event Description
Structure and Function of ARNT
- The aryl hydrocarbon receptor nuclear translocator (ARNT) is a member of the Per-Arnt-Sim (PAS) family of proteins (Gu et al 2000).
- PAS proteins share highly conserved PAS domains (Gu et al 2000).
- PAS proteins act as transcriptional regulators in response to environmental and physiological cues (Gu et al 2000).
- ARNTs have numerous key roles in vertebrates related to responses to developmental and environmental cues.
Isoforms of ARNT:
- Over time ARNT has undergone gene duplication and diversification in vertebrates, which has resulted in three clades of ARNT, namely ARNT1, ARNT2, and ARNT3.
- Each clade can include multiple isoforms and splice variants (Hill et al 2009; Lee et al 2007; Lee et al 2011; Powel & Hahn 2000; Tanguay et al 2000).
- ARNT1s have been demonstrated to function predominantly through heterodimerization with the aryl hydrocarbon receptor (AhR) and hypoxia inducible factor 1 α (HIF1α) (Prasch et al 2004; 2006; Wang et al 1995).
- ARNT2s are believed to function predominantly through heterodimerization with Single Minded (SIM) (Hirose et al 1996).
- ARNT3s, which are also known as ARNT-like (ARNTL), Brain and Muscle ARNT-like-1 (BMAL1), or Morphine Preference 3 (MOP3), are believed to function predominantly through heterodimerization with Circadian Locomotor Output Cycles Kaput (CLOCK) (Gekakis et al 1998).
Roles of ARNTs in mammals:
- ARNT1 functions in normal vascular and hematopoietic development (Kozak et al 1997; Maltepe et al 1997; Abbott & Buckalew 2000).
- ARNT2 functions in development of the hypothalamus and nervous system (Hosoya et al 2001; Keith et al 2001).
- ARNT3 functions in biological rhythms (Gekakis et al 1998).
-
Several isoforms of ARNT have recently been identified in mammalian and aquatic species based on their sequence identity to ARNT. They are grouped into four ARNT types that include: ARNT (HIF-1), ARNT2, BMAL1 (ARNT3, MOP3, JAP3, ARNTL1, TIC), and BMAL2 (ARNT4, ARNTL2, MOP9) (Dougherty et al 2010).
-
Coexpression of ARNT with AhR is crucial for steroid synthesis, secretion, and cellular functions during non-pregnancy, pregnancy, and pseudopregnancy. In ovarian follicles, AhR and ARNT are expressed in the follicular epithelia of primordial and growing follicles, contributing to oocyte maturation and follicular development starting from the primary follicle stage. ARNT also regulates ovarian steroid hormones, such as estradiol and progesterone, impacting ovarian physiology. Knockout studies in mice show that ARNT is essential for embryonic development, with embryos failing to survive beyond day 9.5 due to growth retardation, such findings highlight ARNT's vital role in reproduction and development (Hasan et al 2003, Khorram et al 2002).
Roles of ARNTs in other taxa:
- ARNTs have been demonstrated to have roles in development of the heart, brain, liver, and possibly the peripheral nervous system in zebrafish (Danio rerio) (Hill et al 2009).
- Roles of ARNTs in other taxa have not been sufficiently investigated to date.
Interaction with AHR
- Both ARNT1s and ARNT2s are able to heterodimerize with AhR and interact with dioxin-responsive elements on the DNA in in vitro systems (Hirose et al 1996; Lee et al 2007; Lee et al 2011; Prasch et al 2004).
- Selective knockdown of ARNTs in zebrafish (Danio rerio) demonstrates that ARNT1s, but not ARNT2s, are required for activation of the AhR in vivo (Prasch et al 2004; 2006).
- In limited investigations ARNT3 has not been demonstrated to interact with the AHR either in vivo or in vitro (Jain et al 1998).
Upon ligand binding, the aryl hydrocarbon receptor (AHR) migrates to the nucleus where it dissociates from the cytosolic complex and forms a heterodimer with AHR nuclear translocator (ARNT) (Mimura and Fujii-Kuriyama 2003). The AHR-ARNT complex then binds to a xenobiotic response element (XRE) found in the promoter of an AHR-regulated gene and recruits co-regulators such as CREB binding protein/p300, steroid receptor co-activator (SRC) 1, SRC-2, SRC-3 and nuclear receptor interacting protein 1, leading to induction or repression of gene expression (Fujii-Kuriyama and Kawajiri 2010). Expression levels of several genes, including phase I (e.g. cytochrome P450 (CYP) 1A, CYP1B, CYP2A) and phase II enzymes (e.g. uridine diphosphate glucuronosyl transferase (UDP-GT), glutathione S-transferases (GSTs)), as well as genes involved in cell proliferation (transforming growth factor-beta, interleukin-1 beta), cell cycle regulation (p27, jun-B) and apoptosis (Bax), are regulated through this mechanism (Fujii-Kuriyama and Kawajiri 2010; Giesy et al. 2006; Mimura and Fujii-Kuriyama 2003; Safe 1994).
How It Is Measured or Detected
AhR/ARNT heterodimerization can be measured in several ways:
1) The active AHR complexed with ARNT can be measured using protein-DNA interaction assays. Two methods are described in detail by Perez-Romero and Imperiale (Perez-Romero and Imperiale 2007). Chromatin immunoprecipitation measures the interaction of proteins with specific genomic regions in vivo. It involves the treatment of cells with formaldehyde to crosslink neighboring protein-protein and protein-DNA molecules. Nuclear fractions are isolated, the genomic DNA is sheared, and nuclear lysates are used in immunoprecipitations with an antibody against the protein of interest. After reversal of the crosslinking, the associated DNA fragments are sequenced. Enrichment of specific DNA sequences represents regions on the genome that the protein of interest is associated with in vivo. Electrophoretic mobility shift assay (EMSA) provides a rapid method to study DNA-binding protein interactions in vitro. This relies on the fact that complexes of protein and DNA migrate through a non-denaturing polyacrylamide gel more slowly than free DNA fragments. The protein-DNA complex components are then identified with appropriate antibodies. The EMSA assay was found to be consistent with the luciferase reporter gene assay (in chicken hepatoma cells dosed with dioxin-like compounds (Heid et al. 2001).
2) Species-specific differences in dimerization and differences in dimerization between ARNT isoform and AhR isoform combinations have been assessed through luciferase reporter gene (LRG) assays utilizing COS-7 cells transfected with expression constructs of AhR and ARNT isoforms of mammals, birds, and fishes (Abnet et al 1999; Bak et al 2013; Doering et al 2014; 2015; Hansson & Hahn 2008; Hirose et al 1996; Karchner et al 1999; Lee et al 2007; Lee et al 2011; Prasch et al 2004; Wirgin et al 2011). However, this method is indirect as it also includes binding of a ligand to the AhR, and interaction of the AhR/ARNT heterodimer with dioxin-responsive elements on the DNA.
Domain of Applicability
Taxonomic Presence of ARNT genes:
- ARNTs have been identified in all tetrapods investigated to date (Drutel et al 1996; Hirose et al 1996; Hoffman et al 1991; Lee et al 2007; Lee et al 2011).
- ARNTs have been identified in a great phylogenetic diversity of fishes, including early fishes (Doering et al 2014; 2016).
- ARNT has been identified in investigated invertebrates (Powell-Coffman et al 1998).
Taxonomic Applicability of Heterodimerization of ARNT isoforms with AhR isoforms:
- In mouse (Mus mus) and chicken (Gallus gallus) both the ARNT1 and ARNT2 were capable of heterdimerizing with AHR and interacting with dioxin-responsive elements on the DNA in vitro (Hirose et al 1996; Lee et al 2007; Lee et al 2011; Prasch et al 2004). However, no studies have yet confirmed involvement of both ARNT1 and ARNT2 in vivo.
- In zebrafish, all adverse effects of DLCs so far examined in vivo are mediated solely by ARNT1 based on knockdown studies, although ARNT2 is capable of heterodimerizing with AHR2 and interacting with dioxin-responsive elements on the DNA in vitro (Prasch et al 2004; Prasch et al 2006). In addition to AHRs of zebrafish, AHRs of Atlantic salmon (Salmo salar), Atlantic tomcod (Microgadus tomcod), mummichog, rainbow trout, and red seabream (Pagrus major) have been demonstrated to heterodimerize with ARNT1 in vitro (Abnet et al 1999; Bak et al 2013; Hansson & Hahn 2008; Karchner et al 1999; Wirgin et al 2011), while AHRs of white sturgeon (Acipenser transmontanus), and lake sturgeon (Acipenser fulvescens) have been demonstrated to heterodimerize with ARNT2 in vitro (Doering et al 2014b; 2015b; Prasch et al 2004; 2006).
This mechanism is conserved across species. Mammals possess a single AHR, whereas birds and fish express multiple isoforms, and all three express multiple ARNT isoforms. Not all of the isoforms identified are functionally active. For example, killifish AHR1 and AHR2 are active and display different transcription profiles, whereas zebrafish AHR2 and ARNT2 are active in mediating xenobiotic-mediated toxicity and AHR1 is inactive (Hahn et al. 2006; Prasch et al. 2006).
References
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