Constitutive overexpression of the Drosophila period protein inhibits period mRNA cycling.

Zeng, Hongkui; Hardin, P E; Rosbash, Michael

doi:10.1002/j.1460-2075.1994.tb06666.x

Cited by 213 publications

(201 citation statements)

References 45 publications

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“…2; for each lane compare the distance between the differently migrating variants of PER and a convenient internal size marker). These results are similar to those previously reported for wild-type flies maintained at the standard temperature of 25°C (13,64). Differences in the apparent molecular weight of PER in sodium dodecyl sulfate-polyacrylamide gels are due to the circadian regulation of its phosphorylated state (13).…”

Section: B10supporting

confidence: 90%

“…Indeed, the per protein and RNA cycles have greater amplitudes in LD than in DD (Fig. 3 and 6) (13,26,29,42,64).…”

Section: Discussionmentioning

confidence: 93%

“…In the adult fly head (the anatomical location of the fruit fly circadian pacemaker) (18,21,25,61) the PER and TIM proteins undergo daily fluctuations in abundance (13,31,44,(64)(65)(66), phosphorylation state (13, 65), subcellular distribution (9,31,38,44), and native size (38, 65), consistent with an important role in pacemaker function. PER and TIM form a complex in the cytoplasm (38, 65) that enters the nucleus in a temporally gated manner (9, 38), an event accompanied by the inhibition of per (and probably tim) transcription (28,29,38,42,54,64). Although the biochemical functions of PER and TIM are not known, numerous lines of…”

mentioning

confidence: 94%

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Drosophila melanogaster Deficient in Protein Kinase A Manifests Behavior-Specific Arrhythmia but Normal Clock Function

Majercak

Kalderon

Edery

1997

Molecular and Cellular Biology

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Drosophila melanogaster bearing mutations in the DCO gene, which encodes the major catalytic subunit of cAMP-dependent protein kinase (PKA), displays arrhythmic locomotor activity strongly suggesting a role for PKA in the circadian timing system. This arrhythmicity might result from a requirement for PKA activity in photic resetting pathways, the timekeeping mechanism itself, or downstream effector pathways controlling overt behavioral rhythms. To address these possibilities, we examined the protein and mRNA products from the clock gene period (per) in PKA-deficient flies. The per protein (PER) and mRNA products undergo daily cycles in the heads and bodies of DCO mutants that are indistinguishable from those observed in control wild-type flies. These results indicate that PKA deficiencies affect the proper functioning of elements downstream of the Drosophila timekeeping mechanism. The requirement for PKA in the manifestation of rhythmic activity was preferentially greater in the absence of environmental cycles. However, PKA does not appear to play a universal role in output functions because the clock-controlled eclosion rhythm is normal in DCO mutants. Our results suggest that PKA plays a critical role in the flow of temporal information from circadian pacemaker cells to selective behaviors.A wide variety of organisms display circadian (Х24 h) rhythms ranging from daily fluctuations in cellular biochemistry and physiology to complex behaviors, such as wake-sleep cycles (reviewed in reference 30). These rhythms are governed by endogenous biochemical oscillators (also referred to as clocks or pacemakers) that can be entrained by environmental stimuli, most notably the daily light-dark cycles. This adaptive feature of circadian oscillators enables organisms to maintain temporal alignment between their endogenously driven rhythms and the solar day. The circadian timing system is generally considered to consist of three interconnected parts: (i) input pathways that can receive and transmit external time cues (zeitgebers) to the clock, (ii) the timekeeping mechanism itself, and (iii) downstream effector pathways that are temporally regulated by the clock.Pharmacological and genetic approaches have led to the identification of a diverse set of molecules that have been implicated in each part of the circadian timing system (reviewed in references 10, 50, and 60). Studies using both approaches have suggested that the second messenger cyclic AMP (cAMP) plays a prominent role in the manifestation of circadian rhythms (7,14,16,17,33,39,47,48,59,63). The site of action of cAMP, however, is not clear. For example, in chick pineal cells (47) and the algal flagellate Euglena gracilis (7, 14), cAMP appears to act as an output signal downstream of the oscillator. Conversely, in neural circadian pacemakers cAMP is thought to be involved in light-resetting pathways (16,17,33,39,48). This contention is further supported by the observation that light-induced resetting is correlated with the activation of the cAMP responsive element ...

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Section: B10supporting

confidence: 90%

“…Indeed, the per protein and RNA cycles have greater amplitudes in LD than in DD (Fig. 3 and 6) (13,26,29,42,64).…”

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 94%

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Drosophila melanogaster Deficient in Protein Kinase A Manifests Behavior-Specific Arrhythmia but Normal Clock Function

Majercak

Kalderon

Edery

1997

Molecular and Cellular Biology

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“…We reasoned that such variations, by altering per transcription rate from the UAS construct, might mask PER regulation by the clock. Additionally, expression at 25°C might be too strong, thus overwhelming PER regulatory mechanisms (Zeng et al, 1994;Blanchardon et al, 2001). Indeed, in LD, PER oscillations in the UAS-per16-based larval brain clocks were stronger at 20°C than at 25°C (data not shown).…”

Section: Methodsmentioning

confidence: 94%

A Role for Blind DN2 Clock Neurons in Temperature Entrainment of the Drosophila Larval Brain

Picot¹,

Klarsfeld²,

Chélot³

et al. 2009

Journal of Neuroscience

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Circadian clocks synchronize to the solar day by sensing the diurnal changes in light and temperature. In adult Drosophila, the brain clock that controls rest-activity rhythms relies on neurons showing Period oscillations. Nine of these neurons are present in each larval brain hemisphere. They can receive light inputs through Cryptochrome (CRY) and the visual system, but temperature input pathways are unknown. Here, we investigate how the larval clock network responds to light and temperature. We focused on the CRY-negative dorsal neurons (DN2s), in which light-dark (LD) cycles set molecular oscillations almost in antiphase to all other clock neurons. We first showed that the phasing of the DN2s in LD depends on the pigment-dispersing factor (PDF) neuropeptide in four lateral neurons (LNs), and on the PDF receptor in the DN2s. In the absence of PDF signaling, these cells appear blind, but still synchronize to temperature cycles. Period oscillations in the DN2s were stronger in thermocycles than in LD, but with a very similar phase. Conversely, the oscillations of LNs were weaker in thermocycles than in LD, and were phase-shifted in synchrony with the DN2s, whereas the phase of the three other clock neurons was advanced by a few hours. In the absence of any other functional clock neurons, the PDF-positive LNs were entrained by LD cycles but not by temperature cycles. Our results show that the larval clock neurons respond very differently to light and temperature, and strongly suggest that the CRY-negative DN2s play a prominent role in the temperature entrainment of the network.

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“…PER and TIM proteins accumulate during the night, become phosphorylated, dimerize, and enter the nucleus (14,18,22,29,47,50,56,61,70,76,77), where they negatively regulate transcription of their own mRNAs (11,16,17,26,27,43,63,71,75) and positively regulate transcription of the dClk mRNA (5, 24). Both the negative and positive feedback regulation are thought to result from direct protein-protein interactions of PER and/or TIM with a CLK/CYC transcription factor (11, 37, 71) which, in the absence of PER and TIM, activates transcription of per, tim, and vrille (3,7,11,16,17,24,26,37,43,54,71) and represses the transcription of dClk (15,23,24).…”

mentioning

confidence: 99%

Drosophila doubletime Mutations Which either Shorten or Lengthen the Period of Circadian Rhythms Decrease the Protein Kinase Activity of Casein Kinase I

Preuss

Fan

Kalive

et al. 2004

Molecular and Cellular Biology

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In both mammals and fruit flies, casein kinase I has been shown to regulate the circadian phosphorylation of the period protein (PER). This phosphorylation regulates the timing of PER's nuclear accumulation and decline, and it is necessary for the generation of circadian rhythms. In Drosophila melanogaster, mutations affecting a casein kinase I (CKI) ortholog called doubletime (dbt) can produce short or long periods. The effects of both a short-period (dbt S ) and long-period (dbt L ) mutation on DBT expression and biochemistry were analyzed. Immunoblot analysis of DBT in fly heads showed that both the dbt S and dbt L mutants express DBT at constant levels throughout the day. Glutathione S-transferase pull-down assays and coimmunoprecipitation of DBT and PER showed that wild-type DBT, DBT S , and DBT L proteins can bind to PER equivalently and that these interactions are mediated by the evolutionarily conserved N-terminal part of DBT. However, both the dbt S and dbt L mutations reduced the CKI-7-sensitive kinase activity of an orthologous Xenopus laevis CKI␦ expressed in Escherichia coli. Moreover, expression of DBT in Drosophila S2 cells produced a CKI-7-sensitive kinase activity which was reduced by both the dbt S and dbt L mutations. Thus, lowered enzyme activity is associated with both short-period and long-period phenotypes.Many daily biochemical, physiological, and behavioral processes are termed circadian rhythms because they are temporally regulated by an endogenous circadian clock. While these endogenous clocks are usually synchronized by the environmental light-dark or temperature cycle, in the absence of environmental cues their oscillations persist with a period of approximately 24 h (reviewed in reference 48). A genetic analysis in Drosophila melanogaster, as well as in other model organisms, has revealed much about the molecular components and mechanism of the circadian clock (reviewed in reference 74). Recently, it has become clear that the mammalian circadian clock mechanism is quite similar to the Drosophila mechanism (reviewed in reference 4).Central to the molecular mechanism of Drosophila are the oscillations of the per, tim, and dClk gene products, which drive transcriptional-translational feedback loops (3,5,16,24,27,37,59,60,75; reviewed in reference 72). PER and TIM proteins accumulate during the night, become phosphorylated, dimerize, and enter the nucleus (14,18,22,29,47,50,56,61,70,76,77), where they negatively regulate transcription of their own mRNAs (11,16,17,26,27,43,63,71,75) and positively regulate transcription of the dClk mRNA (5, 24). Both the negative and positive feedback regulation are thought to result from direct protein-protein interactions of PER and/or TIM with a CLK/CYC transcription factor (11, 37, 71) which, in the absence of PER and TIM, activates transcription of per, tim, and vrille (3,7,11,16,17,24,26,37,43,54,71) and represses the transcription of dClk (15,23,24). Entrainment, or synchronization of the clock to light-dark cycles, is conferred in part by a crypt...

show abstract

Constitutive overexpression of the Drosophila period protein inhibits period mRNA cycling.

Cited by 213 publications

References 45 publications

Drosophila melanogaster Deficient in Protein Kinase A Manifests Behavior-Specific Arrhythmia but Normal Clock Function

Drosophila melanogaster Deficient in Protein Kinase A Manifests Behavior-Specific Arrhythmia but Normal Clock Function

A Role for Blind DN2 Clock Neurons in Temperature Entrainment of the Drosophila Larval Brain

Drosophila doubletime Mutations Which either Shorten or Lengthen the Period of Circadian Rhythms Decrease the Protein Kinase Activity of Casein Kinase I

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