@article{ddb18fba97154147bc231bbf70112410,
title = "vrille, Pdp1, and dClock form a second feedback loop in the Drosophila circadian clock",
abstract = "The Drosophila circadian clock consists of two interlocked transcriptional feedback loops. In one loop, dCLOCK/CYCLE activates period expression, and PERIOD protein then inhibits dCLOCK/CYCLE activity. dClock is also rhythmically transcribed, but its regulators are unknown. vrille (vri) and Par Domain Protein 1 (Pdp1) encode related transcription factors whose expression is directly activated by dCLOCK/CYCLE. We show here that VRI and PDP1 proteins feed back and directly regulate dClock expression. Repression of dClock by VRI is separated from activation by PDP1 since VRI levels peak 3-6 hours before PDP1. Rhythmic vri transcription is required for molecular rhythms, and here we show that the clock stops in a Pdp1 null mutant, identifying Pdp1 as an essential clock gene. Thus, VRI and PDP1, together with dClock itself, comprise a second feedback loop in the Drosophila clock that gives rhythmic expression of dClock, and probably of other genes, to generate accurate circadian rhythms.",
author = "Cyran, {Shawn A.} and Buchsbaum, {Anna M.} and Reddy, {Karen L.} and Lin, {Meng Chi} and Glossop, {Nicholas R.J.} and Hardin, {Paul E.} and Young, {Michael W.} and Storti, {Robert V.} and Justin Blau",
note = "Funding Information: The behavioral data in Figure 3 indicated that the correct ratio of VRI:PDP1 is essential for wild-type rhythms and led to the suggestion that VRI and PDP1 compete to regulate the same step in the molecular clock. The finding that VRI and PDP1ϵ can bind exactly the same site in the dClk promoter suggested a molecular mechanism for how the proteins might compete. We tested this idea by transfecting cells with a moderate dose of PDP1ϵ, which activated C3-tk-luc ∼30-fold (Figure 6E) . Cotransfected VRI repressed PDP1ϵ-dependent transactivation. This conclusion is supported by the lack of an effect with the C3m-tk-luc reporter. Thus, VRI and PDP1ϵ compete for binding to the same site in the dClk promoter. The simplest model arising from the data in this figure is that mutations in vri and Pdp1 affect dClk RNA levels in vivo because VRI and PDP1ϵ proteins directly regulate dClk transcription in opposite ways: VRI represses and PDP1ϵ activates the dClk promoter. ",
year = "2003",
month = feb,
day = "7",
doi = "10.1016/S0092-8674(03)00074-6",
language = "English (US)",
volume = "112",
pages = "329--341",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}