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Melatonin is secreted by the pineal gland in a circadian manner as influenced by the <jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>. There is also considerable evidence that melatonin, in turn, acts on the <jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content> directly influencing the circadian \u2018clock\u2019 mechanisms. The most direct route by which melatonin could reach the <jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content> would be via the cerebrospinal fluid of the third ventricle. Melatonin could also reach the pars tuberalis (<jats:styled-content style=\"fixed-case\">PT<\/jats:styled-content>) of the pituitary, another melatonin\u2010sensitive tissue, via this route. The major \u2018clock\u2019 genes include the period genes, <jats:italic>Per1<\/jats:italic> and <jats:italic>Per2<\/jats:italic>, the cryptochrome genes, <jats:italic>Cry1<\/jats:italic> and <jats:italic>Cry2<\/jats:italic>, the <jats:italic>clock<\/jats:italic> (circadian locomotor output cycles kaput) gene, and the <jats:italic>Bmal1<\/jats:italic> (aryl hydrocarbon receptor nuclear translocator\u2010like) gene. Clock and Bmal1 heterodimers act on E\u2010box components of the promoters of the Per and Cry genes to stimulate transcription. A negative feedback loop between the cryptochrome proteins and the nucleus allows the Cry and Per proteins to regulate their own transcription. A cycle of ubiquitination and deubiquitination controls the levels of <jats:styled-content style=\"fixed-case\">CRY<\/jats:styled-content> protein degraded by the proteasome and, hence, the amount of protein available for feedback. Thus, it provides a post\u2010translational component to the circadian clock mechanism. <jats:styled-content style=\"fixed-case\">BMAL<\/jats:styled-content>1 also stimulates transcription of <jats:styled-content style=\"fixed-case\">REV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">ERB<\/jats:styled-content><jats:italic>\u03b1<\/jats:italic> and, in turn, is also partially regulated by negative feedback by <jats:styled-content style=\"fixed-case\">REV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">ERB<\/jats:styled-content><jats:italic>\u03b1<\/jats:italic>. In the \u2018black widow\u2019 model of transcription, proteasomes destroy transcription factors that are needed only for a particular period of time. In the model proposed herein, the interaction of melatonin and the proteasome is required to adjust the <jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content> clock to changes in the environmental photoperiod. In particular, we predict that melatonin inhibition of the proteasome interferes with negative feedback loops (<jats:styled-content style=\"fixed-case\">CRY<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">PER<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">REV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">ERB<\/jats:styled-content><jats:italic>\u03b1<\/jats:italic>) on Bmal1 transcription genes in both the <jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">PT<\/jats:styled-content>. Melatonin inhibition of the proteasome would also tend to stabilize <jats:styled-content style=\"fixed-case\">BMAL<\/jats:styled-content>1 protein itself in the <jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>, particularly at night when melatonin is naturally elevated. Melatonin inhibition of the proteasome could account for the effects of melatonin on circadian rhythms associated with molecular timing genes. The interaction of melatonin with the proteasome in the hypothalamus also provides a model for explaining the dramatic \u2018time of day\u2019 effect of melatonin injections on reproductive status of seasonal breeders. Finally, the model predicts that a proteasome inhibitor such as bortezomib would modify circadian rhythms in a manner similar to melatonin.<\/jats:p>","DOI":"10.1111\/jpi.12189","type":"journal-article","created":{"date-parts":[[2014,11,4]],"date-time":"2014-11-04T08:21:35Z","timestamp":1415089295000},"page":"1-11","source":"Crossref","is-referenced-by-count":227,"title":["Melatonin feedback on clock genes: a theory involving the proteasome"],"prefix":"10.1111","volume":"58","author":[{"given":"Jerry","family":"Vriend","sequence":"first","affiliation":[{"name":"Department of Human Anatomy and Cell Science University of Manitoba Winnipeg MB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russel J.","family":"Reiter","sequence":"additional","affiliation":[{"name":"Department of Cellular and Structural Biology University of Texas Health Science Center San Antonio TX 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