Interactivating Feedback Loops within the Mammalian Clock: BMAL1 Is Negatively Autoregulated and Upregulated by CRY1, CRY2, and PER2

Yu, Wangjie; Nomura, Masahiko; Ikeda, Masaaki

doi:10.1006/bbrc.2001.6300

Cited by 134 publications

(112 citation statements)

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“…1). These three enzymes are targets of PPARα and participate in lipid homeostasis (19,20). Little is known about regulators of the circadian rhythm of lipid metabolism in mouse intestine.…”

Section: Discussionmentioning

confidence: 99%

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CLOCK/BMAL1 is Involved in Lipid Metabolism via Transactivation of the Peroxisome Proliferator-activated Receptor (PPAR) Response Element

Inoue

Shinoda

Ikeda

et al. 2005

JAT

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125

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Lipid absorption and metabolism are regulated by feeding and by the circadian system. It has been suggested that the expression of enzymes involved in lipid metabolism is directly controlled by the clock system. This study was designed to examine whether or not the CLOCK/BMAL1 heterodimer has transcriptional activity for genes via the peroxisome proliferator-activated receptor response element (PPRE).

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Section: Discussionmentioning

confidence: 99%

“…RXRα has been shown to bind to PPARs, resulting in the formation of a heterodimer, which binds to the peroxisome proliferator response element (PPRE), followed by the activation of targets such as acylCoA oxidase (AOX), cellular retinol binding protein II (CRBPII), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase (19,20).…”

Section: Introductionmentioning

confidence: 99%

CLOCK/BMAL1 is Involved in Lipid Metabolism via Transactivation of the Peroxisome Proliferator-activated Receptor (PPAR) Response Element

Inoue

Shinoda

Ikeda

et al. 2005

JAT

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125

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“…The expression vectors encoding human Bmal1 (hBmal1), human Clock (hClock), and mouse Bmal1 (mBmal1) were described previously (Yu et al, 2002). Deletion mutants were generated based on mBmal1 cDNA sequences using the PCR primers listed in Figure 2a.…”

Section: Methodsmentioning

confidence: 99%

Bmal1Is an Essential Regulator for Circadian Cytosolic Ca²⁺Rhythms in Suprachiasmatic Nucleus Neurons

Ikeda

2014

J. Neurosci.

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The hypothalamic suprachiasmatic nucleus (SCN) plays a pivotal role in the mammalian circadian clock system. Bmal1 is a clock gene that drives transcriptional-translational feedback loops (TTFLs) for itself and other genes, and is expressed in nearly all SCN neurons. Despite strong evidence that Bmal1-null mutant mice display arrhythmic behavior under constant darkness, the function of Bmal1 in neuronal activity is unknown. Recently, periodic changes in the levels of intracellular signaling messengers, such as cytosolic Ca 2ϩ and cAMP, were suggested to regulate TTFLs. However, the opposite aspect of how clock gene TTFLs regulate cytosolic signaling remains unclear. To investigate intracellular Ca 2ϩ dynamics under Bmal1 perturbations, we cotransfected some SCN neurons with yellow cameleon together with wild-type or dominant-negative Bmal1 using a gene-gun applied for mouse organotypic cultures. Immunofluorescence staining for a tag protein linked to BMAL1 showed nuclear expression of wild-type BMAL1 and its degradation within 1 week after transfection in SCN neurons. However, dominant-negative BMAL1 did not translocate into the nucleus and the cytosolic signals persisted beyond 1 week. Consistently, circadian Ca 2ϩ rhythms in SCN neurons were inhibited for longer periods by dominant-negative Bmal1 overexpression. Furthermore, SCN neurons transfected with a Bmal1 shRNA lengthened, whereas those overexpressing wild-type Bmal1 shortened, the periods of Ca 2ϩ rhythms, with a significant reduction in their amplitude. BMAL1 expression was intact in the majority of neighboring neurons in organotypic cultures. Therefore, we conclude that proper intrinsic Bmal1 expression, but not passive signaling via cell-to-cell interactions, is the determinant of circadian Ca 2ϩ rhythms in SCN neurons.

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“…The positive limb of the loop is driven by two transcription factors, CLOCK ( [17,18] In the absence of any environmental cue, the PERIOD2 protein is believed to reboost the circadian cycle by stimulating the transcription of bmal1 gene leading to the dimerization with CLOCK and to the reinduction of a new circadian cycle [47][48][49][50][51][52][53][54]. The circadian regulation of the period2 gene has also been linked in vivo to tumor suppression and DNA damage response [55] or the regulation of bone formation by leptin [56].…”

Section: Genes On Which Circadian Clocks Are Runningmentioning

confidence: 99%

Feeding and circadian clocks

Pardini¹,

Kaeffer²

2006

Reprod. Nutr. Dev.

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-The mammalian genome encodes at least a dozen of genes directly involved in the regulation of the feedback loops constituting the circadian clock. The circadian system is built up on a multitude of oscillators organized according to a hierarchical model in which neurons of the suprachiasmatic nuclei of the hypothalamus may drive the central circadian clock and all the other somatic cells may possess the molecular components allowing tissues and organs to constitute peripheral clocks. Suprachiasmatic neurons are driving the central circadian clock which is reset by lighting cues captured and integrated by the melanopsin cells of the retina and define the daily rhythms of locomotor activity and associated physiological regulatory pathways like feeding and metabolism. This central clock entrains peripheral clocks which can be synchronized by non-photic environmental cues and uncoupled from the central one depending on the nature and the strength of the circadian signal. The human circadian clock and its functioning in central or peripheral tissues are currently being explored to increase the therapeutic efficacy of timed administration of drugs or radiation, and to offer better advice on lighting and meal timing useful for frequent travelers suffering from jet lag and for night workers' comfort. However, the molecular mechanism driving and coordinating the central and peripheral clocks through a wide range of synchronizers (lighting, feeding, physical or social activities) remains a mystery. mammals / human / circadian rhythms / nutrients Abbreviations: SCN: suprachiasmatic nuclei, HNF: hepatocyte nuclear factor, TGF-alpha: transforming-growth-factor alpha, NAD(H), NADP(H): nicotinamide adenine dinucleotide (phosphate), NO: nitric oxide.Convention: For a better understanding, genes are written in italics, proteins in capitals.

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Interactivating Feedback Loops within the Mammalian Clock: BMAL1 Is Negatively Autoregulated and Upregulated by CRY1, CRY2, and PER2

Cited by 134 publications

References 38 publications

CLOCK/BMAL1 is Involved in Lipid Metabolism via Transactivation of the Peroxisome Proliferator-activated Receptor (PPAR) Response Element

CLOCK/BMAL1 is Involved in Lipid Metabolism via Transactivation of the Peroxisome Proliferator-activated Receptor (PPAR) Response Element

Bmal1Is an Essential Regulator for Circadian Cytosolic Ca²⁺Rhythms in Suprachiasmatic Nucleus Neurons

Feeding and circadian clocks

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Interactivating Feedback Loops within the Mammalian Clock: BMAL1 Is Negatively Autoregulated and Upregulated by CRY1, CRY2, and PER2

Cited by 134 publications

References 38 publications

CLOCK/BMAL1 is Involved in Lipid Metabolism via Transactivation of the Peroxisome Proliferator-activated Receptor (PPAR) Response Element

CLOCK/BMAL1 is Involved in Lipid Metabolism via Transactivation of the Peroxisome Proliferator-activated Receptor (PPAR) Response Element

Bmal1Is an Essential Regulator for Circadian Cytosolic Ca2+Rhythms in Suprachiasmatic Nucleus Neurons

Feeding and circadian clocks

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Bmal1Is an Essential Regulator for Circadian Cytosolic Ca²⁺Rhythms in Suprachiasmatic Nucleus Neurons