Two basic designs have been described for biological oscillators. The first and simplest is a long negative feedback loop. The second is a negative feedback loop with a positive feedback loop superimposed. Through a combination of computational studies and experimental work, it is now clear that the Cdk/APC oscillator in Xenopus egg extracts belongs to this second class, relying on a bistable positive feedback loop to produce sustained oscillations. Here we propose to explore the generality and potential advantages of this positive-plus-negative feedback design.
The Specific Aims of this project are: 1. To test the hypothesis that positive feedback allows the frequency of cell cycle oscillations to be adjusted without substantially altering the amplitude oscillations. 2. To test the hypothesis that positive feedback allows biochemical signals to propagate across a large cell (like a frog egg) faster than the speed of diffusion. 3. To determine the role of positive feedback in generating sustained oscillations in a somatic cell line. These studies build upon new conceptual advances in the understanding of the systems biology of biological oscillators, and important technical advances in the production of These studies should help us to understand the design principles of the cell cycle oscillator, and of biological oscillators in general.
| Chang, Jeremy B; Ferrell Jr, James E (2013) Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature 500:603-7 |
| Ferrell Jr, James E; Tsai, Tony Yu-Chen; Yang, Qiong (2011) Modeling the cell cycle: why do certain circuits oscillate? Cell 144:874-85 |
| Wolkenhauer, Olaf; Auffray, Charles; Baltrusch, Simone et al. (2010) Systems biologists seek fuller integration of systems biology approaches in new cancer research programs. Cancer Res 70:12-3 |
| Ferrell Jr, James E (2009) Q&A: Cooperativity. J Biol 8:53 |
| Ferrell Jr, James E (2009) Q&A: systems biology. J Biol 8:2 |
| Tsai, Tony Yu-Chen; Choi, Yoon Sup; Ma, Wenzhe et al. (2008) Robust, tunable biological oscillations from interlinked positive and negative feedback loops. Science 321:126-9 |
| Pomerening, Joseph R; Ubersax, Jeffrey A; Ferrell Jr, James E (2008) Rapid cycling and precocious termination of G1 phase in cells expressing CDK1AF. Mol Biol Cell 19:3426-41 |
| Ubersax, Jeffrey A; Ferrell Jr, James E (2006) A noisy 'Start' to the cell cycle. Mol Syst Biol 2:2006.0014 |
