Temporal phosphorylation of the Drosophila period protein.

Edery, Isaac; Zwiebel, Laurence J.; Dembinska, Marie E.; Rosbash, Michael

doi:10.1073/pnas.91.6.2260

Cited by 377 publications

(367 citation statements)

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“…Similar results have not been reported in the mammalian system. to be due to a gradual, circadian phase-dependent phosphorylation of the PER proteins (Edery et al 1994;Lee et al 2001). Interestingly, the timing and extent of the PER phosphorylation are modified in period-altering fly mutants (Edery et al 1994), indicating that the phosphorylation status of the PER proteins reflects the progress in the circadian cycle.…”

Section: Phosphorylation Regulates Subcellular Localizationmentioning

confidence: 99%

Role of Phosphorylation in the Mammalian Circadian Clock

Vanselow¹,

Kramer²

2007

Cold Spring Harbor Symposia on Quantitative Biology

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Circadian clocks regulate a wide variety of processes ranging from gene expression to behavior. At the molecular level, circadian rhythms are thought to be produced by a set of clock genes and proteins interconnected to form transcriptional-translational feedback loops. Rhythmic gene expression was formerly regarded as the major drive for rhythms in clock protein abundance, but recent findings underline the crucial importance of posttranslational mechanisms for both the generation and dynamics of circadian rhythms. In particular, the reversible phosphorylation of PER proteins-essential components within the negative feedback loop in Drosophila and mammals-seems to have a key role for the correct timing of nuclear repression. To understand how PER protein phosphorylation regulates the dynamics of the circadian oscillator, we have mapped endogenous phosphorylation sites in mPER2. Detailed investigation of the functional role of one particular phosphorylation site (Ser-659, which is mutated in the familial advanced sleep phase syndrome [FASPS]) led us propose a model of functionally different phosphorylation sites in PER2. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster.

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Section: Phosphorylation Regulates Subcellular Localizationmentioning

confidence: 99%

Role of Phosphorylation in the Mammalian Circadian Clock

Vanselow¹,

Kramer²

2007

Cold Spring Harbor Symposia on Quantitative Biology

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“…Flies were entrained in LD for 3 d and collected at ZT10 (2 h before lights-off) and ZT22 (2 h before lights-on). PER and TIM levels cycle throughout the day, with maximal expression around ZT22 and low expression at ZT10 (23,24). Because manipulating miR-276a expression has no effect on circadian period, the peak expression time should not change.…”

Section: Significancementioning

confidence: 99%

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

Xiao

Rosbash

2016

Proc. Natl. Acad. Sci. U.S.A.

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Circadian rhythms in metazoan eukaryotes are controlled by an endogenous molecular clock. It functions in many locations, including subsets of brain neurons (clock neurons) within the central nervous system. Although the molecular clock relies on transcription/translation feedback loops, posttranscriptional regulation also plays an important role. Here, we show that the abundant Drosophila melanogaster microRNA mir-276a regulates molecular and behavioral rhythms by inhibiting expression of the important clock gene timeless (tim). Misregulation of mir-276a in clock neurons alters tim expression and increases arrhythmicity under standard constant darkness (DD) conditions. mir-276a expression itself appears to be light-regulated because its levels oscillate under 24-h light-dark (LD) cycles but not in DD. mir-276a is regulated by the transcription activator Chorion factor 2 in flies and in tissue-culture cells. Evidence from flies mutated using the clustered, regularly interspaced, short palindromic repeats (CRISPR) tool shows that mir-276a inhibits tim expression: Deleting the mir276a-binding site in the tim 3′ UTR causes elevated levels of TIM and ∼50% arrhythmicity. We suggest that this pathway contributes to the more robust rhythms observed under light/dark LD conditions than under DD conditions. microRNA | circadian rhythms | light regulation | CRISPR

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“…In vitro experiments, it has been shown that nuclear entry of PER is delayed in the three per L types compared with that in WT flies (Curtin, Huang et al 1995;Lee, Parikh et al 1996) and a larger proportion of PER S are phosphorylated at an earlier time in the morning than PER in per S mutants (Edery, Zwiebel et al 1994). However, as the current model does not include phosphorylation of PER and separation of the nucleus and the cytoplasm, we intend to simulate these experimental findings in a more complete model in future.…”

Section: (Figure 8)mentioning

confidence: 99%