"AHR" redirects here. For other uses, see Ahr (disambiguation).
| Aryl hydrocarbon receptor |
| Identifiers |
| Symbols |
AHR ; bHLHe76 |
| External IDs |
OMIM: 600253 MGI: 105043 HomoloGene: 1224 ChEMBL: 3201 GeneCards: AHR Gene |
| Gene ontology |
| Molecular function |
• DNA binding
• sequence-specific DNA binding transcription factor activity
• RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity
• ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity
• protein binding
• transcription factor binding
• sequence-specific DNA binding
• transcription regulatory region DNA binding
• protein heterodimerization activity
• protein dimerization activity
• Hsp90 protein binding
|
| Cellular component |
• nucleus
• transcription factor complex
• nucleolus
• cytoplasm
• cytosolic aryl hydrocarbon receptor complex
|
| Biological process |
• negative regulation of transcription from RNA polymerase II promoter
• blood vessel development
• regulation of transcription, DNA-dependent
• regulation of transcription from RNA polymerase II promoter
• transcription from RNA polymerase II promoter
• xenobiotic metabolic process
• apoptotic process
• response to stress
• cell cycle
• response to xenobiotic stimulus
• regulation of gene expression
• intracellular receptor signaling pathway
• prostate gland development
• regulation of B cell proliferation
• positive regulation of RNA polymerase II transcriptional preinitiation complex assembly
|
| Sources: Amigo / QuickGO |
|
| Orthologs |
| Species |
Human |
Mouse |
|
| Entrez |
196 |
11622 |
|
| Ensembl |
ENSG00000106546 |
ENSMUSG00000019256 |
|
| UniProt |
P35869 |
P30561 |
|
| RefSeq (mRNA) |
NM_001621 |
NM_013464 |
|
| RefSeq (protein) |
NP_001612 |
NP_038492 |
|
| Location (UCSC) |
Chr 7:
17.34 – 17.39 Mb |
Chr 12:
35.5 – 35.54 Mb |
|
| PubMed search |
[1] |
[2] |
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The aryl hydrocarbon receptor (AhR or AHR) is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a ligand-activated transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. This receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450.
The aryl hydrocarbon receptor is a member of the family of basic helix-loop-helix transcription factors. AHR binds several exogenous ligands such as natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones. Upon ligand binding to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in gene transcription.
Contents
- 1 Protein functional domains
- 2 Ligands
- 3 Signaling pathway
- 3.1 Cytosolic complex
- 3.2 Receptor activation
- 3.3 DNA binding (xenobiotic response element - XRE)
- 4 Functional role in physiology and toxicology
- 4.1 Role in development
- 4.2 Adaptive response
- 4.3 Toxic response
- 5 Protein-protein interactions
- 6 References
- 7 External links
Protein functional domains
The AhR protein contains several domains critical for function and is classified as a member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family of transcription factors.[1][2] The bHLH motif is located in the N-terminal of the protein and is a common entity in a variety of transcription factors.[3] Members of the bHLH superfamily have two functionally distinctive and highly conserved domains. The first is the basic-region (b), which is involved in the binding of the transcription factor to DNA. The second is the helix-loop-helix (HLH) region, which facilitates protein-protein interactions. Also contained with the AhR are two PAS domains, PAS-A and PAS-B, which are stretches of 200-350 amino acids that exhibit a high sequence homology to the protein domains that were originally found in the Drosophila genes period (Per) and single-minded (Sim) and in AhR’s dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT).[4] The PAS domains support specific secondary interactions with other PAS domain containing proteins, as is the case with AhR and ARNT, so that heterozygous and homozygous protein complexes can form. The ligand binding site of AhR is contained within the PAS-B domain[5] and contains several conserved residues critical for ligand binding.[6] Finally, a Q-rich domain is located in the C-terminal region of the protein and is involved in co-activator recruitment and transactivation.[7]
Ligands
Ahr ligands have been generally classified into two categories, synthetic or naturally occurring. The first ligands to be discovered were synthetic and members of the halogenated aromatic hydrocarbons (polychlorinated dibenzodioxins, dibenzofurans and biphenyls) and polycyclic aromatic hydrocarbons (3-methylcholanthrene, benzo(a)pyrene, benzanthracenes and benzoflavones).[8][9] However, recent work has focused on naturally occurring compounds with the hope of identifying an endogenous ligand.
Naturally occurring compounds that have been identified as ligands of Ahr include derivatives of tryptophan such as indigo dye and indirubin,[10] tetrapyrroles such as bilirubin,[11] the arachidonic acid metabolites lipoxin A4 and prostaglandin G,[12] modified low-density lipoprotein[13] and several dietary carotinoids.[9] One assumption made in the search for an endogenous ligand is that the ligand will be a receptor agonist. However, work by Savouret et al. has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.[14]
Signaling pathway
AhR Signaling Pathway - Denison MS, Nagy SR (2003). "Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals". Annu. Rev. Pharmacol. Toxicol. 43: 309-34. *Reprinted, with permission, from the Annual Review of Pharmacology and Toxicology, Volume 43 (c)2003 by Annual Reviews.
[9]
Cytosolic complex
Non-ligand bound Ahr is retained in the cytoplasm as an inactive protein complex consisting of a dimer of Hsp90,[15][16] prostaglandin E synthase 3 (Ptges3, p23)[17][18][19][20] and a single molecule of the immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2),[21] which was previously identified as AhR interacting protein (AIP)[22] and AhR-activated 9 (ARA9).[23] The dimer of Hsp90, along with p23, has a multifunctional role in the protection of the receptor from proteolysis, constraining the receptor in a conformation receptive to ligand binding and preventing the premature binding of ARNT.[5][18][20][24][25][26] XAP2 interacts with carboxyl-terminal of Hsp90 and binds to the AhR nuclear localization sequence (NLS) preventing the inappropriate trafficking of the receptor into the nucleus.[27][28][29]
Receptor activation
Upon ligand binding to AhR, XAP2 is released resulting in exposure of the NLS, which is located in the bHLH region,[30] leading to importation into the nucleus.[31] It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of ARNT.[26][32][33][34] The activated AhR/ARNT heterodimer complex is then capable of either directly and indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes.[26][33][35]
DNA binding (xenobiotic response element - XRE)
The classical recognition motif of the AhR/ARNT complex, referred to as either the AhR-, dioxin- or xenobiotic- responsive element (AHRE, DRE or XRE), contains the core sequence 5’-GCGTG-3’[36] within the consensus sequence 5’-T/GNGCGTGA/CG/CA-3’[37][38] in the promoter region of AhR responsive genes. The AhR/ARNT heterodimer directly binds the AHRE/DRE/XRE core sequence in an asymmetric manner such that ARNT binds to 5’-GTG-3’ and AhR binding 5’-TC/TGC-3’.[39][40] Recent research suggests that a second type of element termed AHRE-II, 5’-CATG(N6)C[T/A]TG-3’, is capable of indirectly acting with the AhR/ARNT complex.[41][42] Regardless of the response element, the end result is a variety of differential changes in gene expression.
Functional role in physiology and toxicology
Role in development
In terms of evolution, the oldest physiological role of Ahr is in development. Ahr is presumed to have evolved from invertebrates where it served a ligand-independent role in normal development processes.[43] The Ahr homolog in Drosophila, spineless (ss) is necessary for development of the distal segments of the antenna and leg.[44][45] Ss dimerizes with tango (tgo), which is the homolog to the mammalian Arnt, to initiate gene transcription. Evolution of the receptor in vertebrates resulted in the ability to bind ligand. In developing vertebrates, Ahr seemingly plays a role in cellular proliferation and differentiation.[46] Despite lacking a clear endogenous ligand, AHR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis,[47] lymphoid systems,[48][49] T-cells,[50] neurons,[51] and hepatocytes.[52] AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion[53] and is involved in megakaryocyte differentiation.[54]
Adaptive response
The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the Ahr signaling pathway.[55][56][57] The search for other metabolizing genes induced by Ahr ligands, due to the presence of DREs, has led to the identification of an "Ahr gene battery" of Phase I and Phase II metabolizing enzymes consisting of CYP1A1, CYP1A2, CYP1B1, NQO1, ALDH3A1, UGT1A2 and GSTA1.[58] Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates Ahr is able to bind and facilitate their biotransformation and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods.[59]
AhR activation seems to be also important for immunological responses and inhibiting inflammation.[49][60]
Toxic response
Extensions of the adaptive response are the toxic responses elicited by Ahr activation. Toxicity results from two different ways of Ahr signaling. The first is a side effect of the adaptive response in which the induction of metabolizing enzymes results in the production of toxic metabolites. For example, the polycyclic aromatic hydrocarbon benzo(a)pyrene (BaP), a ligand for Ahr, induces its own metabolism and bioactivation to a toxic metabolite via the induction of CYP1A1 and CYP1B1 in several tissues.[61] The second approach to toxicity is the result of aberrant changes in global gene transcription beyond those observed in the "Ahr gene battery." These global changes in gene expression lead to adverse changes in cellular processes and function.[62] Microarray analysis has proved most beneficial in understanding and characterizing this response.[46][63][64][65]
Protein-protein interactions
In addition to the protein interactions mentioned above, AhR has also been shown to interact with:
- ARNTL,[66]
- CCNT1,[67]
- ESR1,[68][69]
- NCOA1,[70]
- NEDD8[71]
- NRIP1,[72]
- RELA,[73][74] and
- RP.[75]
References
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- ^ Harrigan JA, Vezina CM, McGarrigle BP, Ersing N, Box HC, Maccubbin AE, Olson JR (February 2004). "DNA adduct formation in precision-cut rat liver and lung slices exposed to benzo[a]pyrene". Toxicol. Sci. 77 (2): 307–14. doi:10.1093/toxsci/kfh030. PMID 14691214.
- ^ Lindén J, Lensu S, Tuomisto J, Pohjanvirta R (October 2010). "Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance". Front Neuroendocrinol 31 (4): 452–78. doi:10.1016/j.yfrne.2010.07.002. PMID 20624415.
- ^ Martinez JM, Afshari CA, Bushel PR, Masuda A, Takahashi T, Walker NJ (2002). "Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells". Toxicol. Sci. 69 (2): 409–23. doi:10.1093/toxsci/69.2.409. PMID 12377990.
- ^ Vezina CM, Walker NJ, Olson JR (2004). "Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression". Environ. Health Perspect. 112 (16): 1636–44. doi:10.1289/ehp.7253. PMC 1247661. PMID 15598615.
- ^ Ovando BJ, Vezina CM, McGarrigle BP, Olson JR (2006). "Hepatic gene downregulation following acute and subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin". Toxicol. Sci. 94 (2): 428–38. doi:10.1093/toxsci/kfl111. PMID 16984957.
- ^ Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (1997). "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 (13): 8581–93. doi:10.1074/jbc.272.13.8581. PMID 9079689.
- ^ Tian Y, Ke S, Chen M, Sheng T (2003). "Interactions between the aryl hydrocarbon receptor and P-TEFb. Sequential recruitment of transcription factors and differential phosphorylation of C-terminal domain of RNA polymerase II at cyp1a1 promoter". J. Biol. Chem. 278 (45): 44041–8. doi:10.1074/jbc.M306443200. PMID 12917420.
- ^ Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S (2003). "The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes". Mol. Cell. Biol. 23 (6): 1843–55. doi:10.1128/MCB.23.6.1843-1855.2003. PMC 149455. PMID 12612060.
- ^ Klinge CM, Kaur K, Swanson HI (2000). "The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1". Arch. Biochem. Biophys. 373 (1): 163–74. doi:10.1006/abbi.1999.1552. PMID 10620335.
- ^ Beischlag TV, Wang S, Rose DW, Torchia J, Reisz-Porszasz S, Muhammad K, Nelson WE, Probst MR, Rosenfeld MG, Hankinson O (2002). "Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex". Mol. Cell. Biol. 22 (12): 4319–33. doi:10.1128/MCB.22.12.4319-4333.2002. PMC 133867. PMID 12024042.
- ^ Antenos M, Casper RF, Brown TJ (2002). "Interaction with Nedd8, a ubiquitin-like protein, enhances the transcriptional activity of the aryl hydrocarbon receptor". J. Biol. Chem. 277 (46): 44028–34. doi:10.1074/jbc.M202413200. PMID 12215427.
- ^ Kumar MB, Tarpey RW, Perdew GH (1999). "Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs". J. Biol. Chem. 274 (32): 22155–64. doi:10.1074/jbc.274.32.22155. PMID 10428779.
- ^ Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE (2000). "The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells". Oncogene 19 (48): 5498–506. doi:10.1038/sj.onc.1203945. PMID 11114727.
- ^ Ruby CE, Leid M, Kerkvliet NI (2002). "2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses tumor necrosis factor-alpha and anti-CD40-induced activation of NF-kappaB/Rel in dendritic cells: p50 homodimer activation is not affected". Mol. Pharmacol. 62 (3): 722–8. doi:10.1124/mol.62.3.722. PMID 12181450.
- ^ Ge NL, Elferink CJ (1998). "A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle". J. Biol. Chem. 273 (35): 22708–13. doi:10.1074/jbc.273.35.22708. PMID 9712901.
External links
- Aryl hydrocarbon receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
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Transcription factors and intracellular receptors
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(1) Basic domains
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| (1.1) Basic leucine zipper (bZIP) |
- Activating transcription factor
- AP-1
- c-Fos
- FOSB
- FOSL1
- FOSL2
- JDP2
- c-Jun
- JUNB
- JunD
- BACH
- BATF
- BLZF1
- C/EBP
- CREB
- CREM
- DBP
- DDIT3
- GABPA
- HLF
- MAF
- NFE
- NFIL3
- NRL
- NRF
- XBP1
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| (1.2) Basic helix-loop-helix (bHLH) |
- ATOH1
- AhR
- AHRR
- ARNT
- ASCL1
- BHLH
- ARNTL
- CLOCK
- EPAS1
- FIGLA
- HAND
- HES
- HEY
- HES1
- HIF
- ID
- LYL1
- MESP2
- MXD4
- MYCL1
- MYCN
- Myogenic regulatory factors
- Neurogenins
- NeuroD
- NPAS
- OLIG
- Pho4
- Scleraxis
- SIM
- TAL
- Twist
- USF1
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| (1.3) bHLH-ZIP |
- AP-4
- MAX
- MITF
- MNT
- MLX
- MXI1
- Myc
- SREBP
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| (1.4) NF-1 |
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| (1.5) RF-X |
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| (1.6) Basic helix-span-helix (bHSH) |
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(2) Zinc finger DNA-binding domains
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| (2.1) Nuclear receptor (Cys4) |
| subfamily 1 |
- Thyroid hormone
- CAR
- FXR
- LXR
- PPAR
- PXR
- RAR
- ROR
- Rev-ErbA
- VDR
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| subfamily 2 |
- COUP-TF
- Ear-2
- HNF4
- PNR
- RXR
- Testicular receptor
- TLX
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| subfamily 3 |
- Steroid hormone
- Androgen
- Estrogen
- Glucocorticoid
- Mineralocorticoid
- Progesterone
- Estrogen related
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| subfamily 4 |
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| subfamily 5 |
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| subfamily 6 |
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| subfamily 0 |
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| (2.2) Other Cys4 |
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| (2.3) Cys2His2 |
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| (2.4) Cys6 |
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| (2.5) Alternating composition |
- AIRE
- DIDO1
- GRLF1
- ING
- JARID
- JMJD1B
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| (2.6) WRKY |
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(3) Helix-turn-helix domains
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(4) β-Scaffold factors with minor groove contacts
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| (4.1) Rel homology region |
- NF-κB
- NFKB1
- NFKB2
- REL
- RELA
- RELB
- NFAT
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| (4.2) STAT |
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| (4.3) p53 |
- p53
- TBX
- 1
- 2
- 3
- 5
- 19
- 21
- 22
- TBR1
- TBR2
- TFT
- MYRF
- TP63
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| (4.4) MADS box |
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| (4.6) TATA-binding proteins |
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| (4.7) High-mobility group |
- BBX
- HMGB
- HMGN
- HNF
- LEF1
- SOX
- 1
- 2
- 3
- 4
- 5
- 6
- 8
- 9
- 10
- 11
- 12
- 13
- 14
- 15
- 18
- 21
- SRY
- SSRP1
- TCF
- TOX
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| (4.9) Grainyhead |
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| (4.10) Cold-shock domain |
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| (4.11) Runt |
- CBF
- CBFA2T2
- CBFA2T3
- RUNX1
- RUNX2
- RUNX3
- RUNX1T1
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(0) Other transcription factors
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| (0.2) HMGI(Y) |
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| (0.3) Pocket domain |
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| (0.5) AP-2/EREBP-related factors |
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| (0.6) Miscellaneous |
- ARID
- CAP
- IFI
- MLL
- MNDA
- NFY
- Rho/Sigma
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see also transcription factor/coregulator deficiencies
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
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