Metabolism and Cancer: The Circadian Clock Connection

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Circadian clocks are present in almost all mammalian tissues. The master or central clock is located in the hypothalamic suprachiasmatic nucleus (SCN), a small brain region containing 10,000–15,000 neurons. The SCN clock can function autonomously, without any external input, but it can be reset by environmental cues such as light. Clocks outside the SCN are referred to as peripheral clocks and are thought to be synchronized by the master clock to ensure temporally coordinated physiology.[6]?The synchronization mechanisms implicate various humoral signals, including circulating entraining factors such as glucocorticoids.[17]?Moreover, peripheral clocks, such as the liver, can be synchronized by the availability of metabolites or feeding time.[18]?Peripheral clocks are present in almost all mammalian tissues, such as the liver, heart, lungs and kidneys, where they maintain circadian rhythms and modulate transcription factors in a paracrine fashion to regulate tissue-specific gene expression. For example, the liver clock controls the expression of several metabolic genes, such as phosphoenolpyruvate carboxykinase 2 (?PCK2?; which encodes a gluconeogenic enzyme), the activityof which is decreased in hepatic cancer.[19]
The Negative Feedback Loop
From a molecular standpoint, circadian rhythms are regulated by transcriptional and post-translational feedback loops generated by a set of interplaying clock proteins (Fig. 1). The fundamental mechanism of the generation and maintenance of rhythms is similar in the central and the peripheral clocks; however, the output pathways elicited can be different and more tissue specific. The positive limb of the mammalian clock machinery is comprised ofCLOCK?and?BMAL1, which are transcription factors that heterodimerize through the PAS domain and induce the expression of clock-controlled genes by binding to their promoters at E-boxes. The cryptochrome (?CRY1?and?CRY2?) and period (?PER1?,?PER2?and?PER3?) families are clock-controlled genes and encode proteins that negatively regulate the circadian machinery. Per and Cry proteins are thought to translocate into the nucleus and form a complex to inhibit CLOCK–BMAL1-mediated transcription, thereby closing the negative feedback loop.[6]?To start a new transcription cycle, the CLOCK–BMAL1 complex needs to be de-repressed through the proteolytic degradation of Per and Cry. Although we have described the mammalian circadian clocks, the generation and maintenance of rhythms is conceptually conserved in other model organisms such as?Drosophila melanogaster,?Neurospora crassa?and plants
Metabolism and Cancer: The Circadian Clock ConnectionOriginally from: http://www.nursinglink.monster.com/news/articles/15121-metabolism-and-cancer-the-circadian-clock-connection

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