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Aryl hydrocarbon receptor nuclear translocator-like
Identifiers
Symbols ARNTL; BMAL1; BMAL1c; JAP3; MGC47515; MOP3; PASD3; TIC
External IDs OMIM602550 MGI1096381 HomoloGene910 GeneCards: ARNTL Gene
RNA expression pattern
PBB GE ARNTL 210971 s at tn.png
PBB GE ARNTL 209824 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 406 11865
Ensembl ENSG00000133794 ENSMUSG00000055116
UniProt O00327 Q3UHZ2
RefSeq (mRNA) NM_001030272 NM_007489
RefSeq (protein) NP_001025443 NP_031515
Location (UCSC) Chr 11:
13.26 - 13.37 Mb
Chr 7:
113 - 113.11 Mb
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

Function

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.

Species distribution

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.

Knockout studies and clinical significance

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]

Regulation

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]

See also


Interactions

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]

References

  1. ^ a b c d e Hogenesch JB, Gu YZ, Jain S, Bradfield CA (1998). "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors". Proc. Natl. Acad. Sci. U.S.A. 95 (10): 5474–9. doi:10.1073/pnas.95.10.5474. PMID 9576906.  
  2. ^ Gekakis N, Staknis D, Nguyen HB, et al. (1998). "Role of the CLOCK protein in the mammalian circadian mechanism". Science 280 (5369): 1564–9. doi:10.1126/science.280.5369.1564. PMID 9616112.  
  3. ^ Kume K, Zylka MJ, Sriram S, et al. (1999). "mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop". Cell 98 (2): 193–205. doi:10.1016/S0092-8674(00)81014-4. PMID 10428031.  
  4. ^ Griffin EA, Staknis D, Weitz CJ (1999). "Light-independent role of CRY1 and CRY2 in the mammalian circadian clock". Science 286 (5440): 768–71. doi:10.1126/science.286.5440.768. PMID 10531061.  
  5. ^ Lowrey PL, Shimomura K, Antoch MP, et al. (2000). "Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau". Science 288 (5465): 483–92. doi:10.1126/science.288.5465.483. PMID 10775102.  
  6. ^ Sato TK, Yamada RG, Ukai H, et al. (2006). "Feedback repression is required for mammalian circadian clock function". Nat. Genet. 38 (3): 312–9. doi:10.1038/ng1745. PMID 16474406.  
  7. ^ Cermakian N, Whitmore D, Foulkes NS, Sassone-Corsi P (April 2000). "Asynchronous oscillations of two zebrafish CLOCK partners reveal differential clock control and function". Proceedings of the National Academy of Sciences of the United States of America 97 (8): 4339–44. doi:10.1073/pnas.97.8.4339. PMID 10760301.  
  8. ^ Okano T, Yamamoto K, Okano K, et al. (September 2001). "Chicken pineal clock genes: implication of BMAL2 as a bidirectional regulator in circadian clock oscillation". Genes to cells : devoted to molecular & cellular mechanisms 6 (9): 825–36. PMID 11554928. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1356-9597&date=2001&volume=6&issue=9&spage=825.  
  9. ^ Rutila JE, Suri V, Le M, So WV, Rosbash M, Hall JC (May 1998). "CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless". Cell 93 (5): 805–14. doi:10.1016/S0092-8674(00)81441-5. PMID 9630224.  
  10. ^ Ikeda M, Nomura M (1997). "cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage". Biochem. Biophys. Res. Commun. 233 (1): 258–64. doi:10.1006/bbrc.1997.6371. PMID 9144434.  
  11. ^ Bunger MK, Wilsbacher LD, Moran SM, et al. (2000). "Mop3 is an essential component of the master circadian pacemaker in mammals". Cell 103 (7): 1009–17. doi:10.1016/S0092-8674(00)00205-1. PMID 11163178.  
  12. ^ Boden MJ, Kennaway DJ (2006). "Circadian rhythms and reproduction". Reproduction 132 (3): 379–92. doi:10.1530/rep.1.00614. PMID 16940279.  
  13. ^ Kondratov RV (2007). "A role of the circadian system and circadian proteins in aging". Ageing Res. Rev. 6 (1): 12–27. doi:10.1016/j.arr.2007.02.003. PMID 17369106.  
  14. ^ Bunger MK, Walisser JA, Sullivan R, et al. (2005). "Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus". Genesis 41 (3): 122–32. doi:10.1002/gene.20102. PMID 15739187.  
  15. ^ Rudic RD, McNamara P, Curtis AM, et al. (2004). "BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis". PLoS Biol. 2 (11): e377. doi:10.1371/journal.pbio.0020377. PMID 15523558.  
  16. ^ Turek FW, Joshu C, Kohsaka A, et al. (2005). "Obesity and metabolic syndrome in circadian Clock mutant mice". Science 308 (5724): 1043–5. doi:10.1126/science.1108750. PMID 15845877.  
  17. ^ Partonen T, Treutlein J, Alpman A, et al. (2007). "Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression". Ann. Med. 39 (3): 229–38. doi:10.1080/07853890701278795. PMID 17457720.  
  18. ^ Preitner N, Damiola F, Lopez-Molina L,et al. (2002). "The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator". Cell 110 (2): 251–60. doi:10.1016/S0092-8674(02)00825-5. PMID 12150932.  
  19. ^ a b c Akashi M, Takumi T (May 2005). "The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1". Nature structural & molecular biology 12 (5): 441–8. doi:10.1038/nsmb925. PMID 15821743.  
  20. ^ a b c Guillaumond F, Dardente H, Giguère V, Cermakian N (October 2005). "Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors". Journal of biological rhythms 20 (5): 391–403. doi:10.1177/0748730405277232. PMID 16267379.  
  21. ^ Sato TK, Panda S, Miraglia LJ, et al. (2004). "A functional genomics strategy reveals Rora as a component of the mammalian circadian clock". Neuron 43 (4): 527–37. doi:10.1016/j.neuron.2004.07.018. PMID 15312651.  
  22. ^ Shearman LP, Sriram S, Weaver DR, et al. (2000). "Interacting molecular loops in the mammalian circadian clock". Science 288 (5468): 1013–9. doi:10.1126/science.288.5468.1013. PMID 10807566.  
  23. ^ Ueda HR, Hayashi S, Chen W, et al. (February 2005). "System-level identification of transcriptional circuits underlying mammalian circadian clocks". Nature genetics 37 (2): 187–92. doi:10.1038/ng1504. PMID 15665827.  
  24. ^ Liu AC, Tran HG, Zhang EE, Priest AA, Welsh DK, Kay SA (February 2008). "Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms". PLoS genetics 4 (2): e1000023. doi:10.1371/journal.pgen.1000023. PMID 18454201.  
  25. ^ Ooe, Norihisa; Saito Koichi, Mikami Nobuyoshi, Nakatuka Iwao, Kaneko Hideo (Jan. 2004). "Identification of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 competitive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression". Mol. Cell. Biol. (United States) 24 (2): 608–16. doi:10.1128/MCB.24.2.608-616.2004. ISSN 0270-7306. PMID 14701734.  
  26. ^ a b McNamara, P; Seo S B, Rudic R D, Sehgal A, Chakravarti D, FitzGerald G A (Jun. 2001). "Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock". Cell (United States) 105 (7): 877–89. doi:10.1016/S0092-8674(01)00401-9. ISSN 0092-8674. PMID 11439184.  
  27. ^ Hogenesch, J B; Chan W K, Jackiw V H, Brown R C, Gu Y Z, Pray-Grant M, Perdew G H, Bradfield C A (Mar. 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. (UNITED STATES) 272 (13): 8581–93. doi:10.1074/jbc.272.13.8581. ISSN 0021-9258. PMID 9079689.  
  28. ^ Lee, Jiwon; Lee Yool, Lee Min Joo, Park Eonyoung, Kang Sung Hwan, Chung Chin Ha, Lee Kun Ho, Kim Kyungjin (Oct. 2008). "Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex". Mol. Cell. Biol. (United States) 28 (19): 6056–65. doi:10.1128/MCB.00583-08. PMID 18644859.  

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