This proposal studies how protein phosphorylation regulates the period of the circadian clock within mammalian cells. Circadian rhythms are a circa-24 hour cycle that regulates key biological processes. Daily fluctuations of wakefulness, stress hormones, lipid metabolism, immune function and the cell division cycle are controlled by the molecular clocks that function throughout our bodies. Mutations in regulatory components of the clock can shorten or lengthen the timing of the rhythms and have significant physiological consequences. The clock is formed by a negative feedback loop of transcription, translation, and inhibition of transcription. The precision of clock timing is controlled by protein kinases and phosphatases. Casein kinase I epsilon is a protein kinase that regulates the circadian clock by periodic phosphorylation of the proteins PER1 and PER2, controlling their stability and localization. In this proposal, the role of phosphorylation in regulating PER function in the clock is explored in detail. Quantitative modeling has proven very useful in making important predictions about how changes in phosphorylation alter the clock's behavior. We will use data from these studies to refine our quantitative model and make additional testable predictions. A detailed understanding of how reversible protein phosphorylation regulates circadian rhythms and a detailed quantitative model that makes clear, testable and accurate predictions about the clock and how we may manipulate it, can have important benefits for human health. Pharmacological manipulation of rhythms could mitigate stress from jet lag, shift work, and perhaps even seasonal affective disorder.
| Peterson, Christopher W; Ayer, Donald E (2011) An extended Myc network contributes to glucose homeostasis in cancer and diabetes. Front Biosci (Landmark Ed) 16:2206-23 |
| Stoltzman, Carrie A; Kaadige, Mohan R; Peterson, Christopher W et al. (2011) MondoA senses non-glucose sugars: regulation of thioredoxin-interacting protein (TXNIP) and the hexose transport curb. J Biol Chem 286:38027-34 |
| Forger, Daniel B (2011) Signal processing in cellular clocks. Proc Natl Acad Sci U S A 108:4281-5 |
| Ko, Caroline H; Yamada, Yujiro R; Welsh, David K et al. (2010) Emergence of noise-induced oscillations in the central circadian pacemaker. PLoS Biol 8:e1000513 |
| Sloan, Elizabeth J; Ayer, Donald E (2010) Myc, mondo, and metabolism. Genes Cancer 1:587-96 |
| Yamada, Yr; Forger, Db (2010) Multiscale complexity in the mammalian circadian clock. Curr Opin Genet Dev 20:626-33 |
| Peterson, Christopher W; Stoltzman, Carrie A; Sighinolfi, Michael P et al. (2010) Glucose controls nuclear accumulation, promoter binding, and transcriptional activity of the MondoA-Mlx heterodimer. Mol Cell Biol 30:2887-95 |
| Kaadige, Mohan R; Looper, Ryan E; Kamalanaadhan, Sadhaasivam et al. (2009) Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity. Proc Natl Acad Sci U S A 106:14878-83 |
| Stoltzman, Carrie A; Peterson, Christopher W; Breen, Kevin T et al. (2008) Glucose sensing by MondoA:Mlx complexes: a role for hexokinases and direct regulation of thioredoxin-interacting protein expression. Proc Natl Acad Sci U S A 105:6912-7 |
| Virshup, D M; Eide, E J; Forger, D B et al. (2007) Reversible protein phosphorylation regulates circadian rhythms. Cold Spring Harb Symp Quant Biol 72:413-20 |
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