Aryl hydrocarbon receptor nuclear translocator-like, also known as ARNTL, Bmal1, or Mop3, is a
The protein encoded by this gene is a
basic-helix-loop-helixPAS (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-boxresponse elementscite journal |author=Hogenesch JB, Gu YZ, Jain S, Bradfield CA |title=The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue=10 |pages=5474–9 |year=1998 |pmid=9576906 |doi=] in promoter regions of many genes including two families of repressor proteins, the Per genescite journal |author=Gekakis N, Staknis D, Nguyen HB, "et al" |title=Role of the CLOCK protein in the mammalian circadian mechanism |journal=Science |volume=280 |issue=5369 |pages=1564–9 |year=1998 |pmid=9616112 |doi=] (Per1, Per2, Per3) and the Cryptochromescite journal |author=Kume K, Zylka MJ, Sriram S, "et al" |title=mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop |journal=Cell |volume=98 |issue=2 |pages=193–205 |year=1999 |pmid=10428031 |doi=] cite journal |author=Griffin EA, Staknis D, Weitz CJ |title=Light-independent role of CRY1 and CRY2 in the mammalian circadian clock |journal=Science |volume=286 |issue=5440 |pages=768–71 |year=1999 |pmid=10531061 |doi=] (Cry1 and Cry2). These repressor proteins are translated, and bind in a complex with casein kinase one epsiloncite journal |author=Lowrey PL, Shimomura K, Antoch MP, "et al" |title=Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau |journal=Science |volume=288 |issue=5465 |pages=483–92 |year=2000 |pmid=10775102 |doi=] (Csnk1e) and delta (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 Cryptochromescite journal |author=Sato TK, Yamada RG, Ukai H, "et al" |title=Feedback repression is required for mammalian circadian clock function |journal=Nat. Genet. |volume=38 |issue=3 |pages=312–9 |year=2006 |pmid=16474406 |doi=10.1038/ng1745] . 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.
Three transcript variants encoding two different isoforms have been found for this gene.cite journal |author=Ikeda M, Nomura M |title=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 |journal=Biochem. Biophys. Res. Commun. |volume=233 |issue=1 |pages=258–64 |year=1997 |pmid=9144434 |doi=10.1006/bbrc.1997.6371] 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.cite journal |author=Bunger MK, Wilsbacher LD, Moran SM, "et al" |title=Mop3 is an essential component of the master circadian pacemaker in mammals |journal=Cell |volume=103 |issue=7 |pages=1009–17 |year=2000 |pmid=11163178 |doi=] In addition to defects in the clock, these Arntl null-mice also have reproductive problemscite journal |author=Boden MJ, Kennaway DJ |title=Circadian rhythms and reproduction |journal=Reproduction |volume=132 |issue=3 |pages=379–92 |year=2006 |pmid=16940279 |doi=10.1530/rep.1.00614] , are small in stature, age quicklycite journal |author=Kondratov RV |title=A role of the circadian system and circadian proteins in aging |journal=Ageing Res. Rev. |volume=6 |issue=1 |pages=12–27 |year=2007 |pmid=17369106 |doi=10.1016/j.arr.2007.02.003] , and have progressive arthropathycite journal |author=Bunger MK, Walisser JA, Sullivan R, "et al" |title=Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus |journal=Genesis |volume=41 |issue=3 |pages=122–32 |year=2005 |pmid=15739187 |doi=10.1002/gene.20102] that results in having less overall locomotor activity than wild type mice. Recent phenotyping data suggests that this genecite journal |author=Rudic RD, McNamara P, Curtis AM, "et al" |title=BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis |journal=PLoS Biol. |volume=2 |issue=11 |pages=e377 |year=2004 |pmid=15523558 |doi=10.1371/journal.pbio.0020377] and its partner Clockcite journal |author=Turek FW, Joshu C, Kohsaka A, "et al" |title=Obesity and metabolic syndrome in circadian Clock mutant mice |journal=Science |volume=308 |issue=5724 |pages=1043–5 |year=2005 |pmid=15845877 |doi=10.1126/science.1108750] also play a role in regulation of glucose homeostasis and metabolism. Finally, Arntl, Npas2, and Per2 have been associated with
seasonal affective disorderin humanscite journal |author=Partonen T, Treutlein J, Alpman A, "et al" |title=Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression |journal=Ann. Med. |volume=39 |issue=3 |pages=229–38 |year=2007 |pmid=17457720 |doi=10.1080/07853890701278795] .
Arntl transcription is circadian and reciprocally regulated by NR1D1cite journal |author=Preitner N, Damiola F, Lopez-Molina L, "et al" |title=The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator |journal=Cell |volume=110 |issue=2 |pages=251–60 |year=2002 |pmid=12150932 |doi=] (Rev-erb-alpha) and
RORAcite journal |author=Sato TK, Panda S, Miraglia LJ, "et al" |title=A functional genomics strategy reveals Rora as a component of the mammalian circadian clock |journal=Neuron |volume=43 |issue=4 |pages=527–37 |year=2004 |pmid=15312651 |doi=10.1016/j.neuron.2004.07.018] , which establishes a second interlocking loopcite journal |author=Shearman LP, Sriram S, Weaver DR, "et al" |title=Interacting molecular loops in the mammalian circadian clock |journal=Science |volume=288 |issue=5468 |pages=1013–9 |year=2000 |pmid=10807566 |doi=] in the mammalian circadian clock.
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