| Aryl hydrocarbon receptor nuclear translocator-like | |||||||||||||
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| Identifiers | |||||||||||||
| Symbols | ARNTL; BMAL1; BMAL1c; JAP3; MGC47515; MOP3; PASD3; TIC; bHLHe5 | ||||||||||||
| External IDs | OMIM: 602550 MGI: 1096381 HomoloGene: 910 GeneCards: ARNTL Gene | ||||||||||||
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| RNA expression pattern | |||||||||||||
| More reference expression data | |||||||||||||
| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 406 | 11865 | |||||||||||
| Ensembl | ENSG00000133794 | ENSMUSG00000055116 | |||||||||||
| UniProt | O00327 | Q3UHZ2 | |||||||||||
| RefSeq (mRNA) | NM_001030272.1 | NM_007489.3 | |||||||||||
| RefSeq (protein) | NP_001025443.1 | NP_031515.1 | |||||||||||
| Location (UCSC) | Chr 11: 13.3 – 13.41 Mb |
Chr 7: 120.35 – 120.46 Mb |
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| PubMed search | [1] | [2] | |||||||||||
Aryl hydrocarbon receptor nuclear translocator-like, also known as ARNTL, Bmal1, or Mop3, is a gene which is associated with susceptibility to hypertension and type 2 diabetes.
Contents |
The protein encoded by this gene is a basic helix-loop-helix PAS (bHLH-PAS) domain containing protein that forms a heterodimer with a second bHLH-PAS protein, Clock, or its ortholog, Npas2. This complex binds to E-box response elements[1] in promoter regions of many genes including those encoding the Period (Per1, Per2, Per3)[2] and Cryptochrome (Cry1 and Cry2) [3][4] proteins. These repressor proteins are translated, and bind in a complex with casein kinase 1ε (Csnk1e)[5] and 1δ (Csnk1d). Next, the entire complex translocates to the nucleus, where it interacts with the Arntl/Clock heterodimer to inhibit its transactivation. This hypothesis is supported by the observation that point mutants in the Arntl or Clock render them resistant to interaction and repression by Cryptochromes.[6] Transcription of Period and Cryptochrome genes, therefore, is inhibited, the protein levels of Period and Cryptochrome genes drop, and eventually repression is relieved to allow their transcription to build up again. This process occurs with a period length of approximately 24 hours.
In addition to mammals like mice or humans, homologs of the Arntl gene are found in fish,[7] birds[8] and in the fruit fly Drosophila (the fly homolog, cycle, encodes a proteins that lacks a homologous C-terminal domains, but as in mammals it acts as a partner of the CLOCK protein).[9] In humans, three transcript variants encoding two different isoforms have been found for this gene.[10] The importance of these transcript variants is unknown.
Arntl (or Bmal1 or Mop3) is the only component of the mammalian circadian clock whose sole deletion in a mouse model generates arrhythmicity.[11] In addition to defects in the clock, these Arntl null-mice also have reproductive problems,[12] are small in stature, age quickly,[13] and have progressive arthropathy[14] that results in having less overall locomotor activity than wild type mice. Recent phenotyping data suggests that this gene[15] and its partner Clock[16] also play a role in regulation of glucose homeostasis and metabolism. Finally, Arntl, Npas2, and Per2 have been associated with seasonal affective disorder in humans.[17]
Arntl transcription is circadian and reciprocally regulated by the orphan nuclear receptors NR1D1 (Rev-erb-α)[18][19][20] and NR1F1 (ROR-α)[19][20][21] which establishes a second interlocking loop[22] in the mammalian circadian clock. The other nuclear receptors of the same families (NR1D2 or Rev-erb-β; NR1F2 or ROR-β; NR1F3 or ROR-γ) were also shown to act on Arntl gene.[19][20][23][24]
ARNTL has been shown to interact with HIF1A,[1] CLOCK,[1][25][26] Aryl hydrocarbon receptor,[27] SUMO3,[28] EPAS1[1] and NPAS2.[1][26]
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