We have been studying two signaling systems that regulate M-phase entry and progression. The first is the Mos- MEK-p42 MAPK cascade, which is an important element in the network that triggers Xenopus oocyte maturation. In oocytes, this cascade is embedded in two positive feedback loops--active p42 MAPK brings about the accumulation and activation of Mos and Raf-l--and this feedback allows the cascade to convert transient, graded stimuli into sustained, switch-like responses. Recently we identified a role for Mos outside of oocyte maturation: Mos is the long-sought-after mitotic activator of p42 MAPK in Xenopus egg extracts. Moreover, the activity of Mos was found to depend upon one or more Cdc2- cyclin B-dependent phosphorylations, a previously unrecognized level of Mos regulation. These findings provide the first evidence of a mitotic role for Mos, and the first evidence that Mos activity is post-translationally regulated. Here we propose: (1) to elucidate the mechanism through which Cdc2-cyclin B stimulates Mos activity. The second system we have been studying is the Cdc2/cyclin B-Wee1-Cdc25-APC network. Like the Mos-MEKp42 MAPK cascade, this network contains a system of interlocking positive feedback loops. The positive feedback loops function as a bistable trigger for mitosis, and together with a slower negative feedback loop that triggers cyclin destruction, function as a reliable biochemical oscillator. Here we propose: (2) To determine whether three """"""""open loop"""""""" subcircuits of the Cdc2/cyclin B-Weel-Cdc25-APC network exhibits steeply sigmoidal responses, which recent theoretical work indicates should be important for robust bistability in """"""""closed loop"""""""" feedback systems, and (3) To determine whether the bistability of Cdc2 activation is required for sustained cell cycle oscillations. Our overarching goals are to gain new insights into the biochemical circuits that regulate M-phase progression, and to better understand the design principles used by nature in the generation of sophisticated, systems-level biochemical behaviors.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Reproductive Biology Study Section (REB)
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Zatz, Marion M
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Stanford University
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Santos, Silvia D M; Wollman, Roy; Meyer, Tobias et al. (2012) Spatial positive feedback at the onset of mitosis. Cell 149:1500-13
Ferrell Jr, James E (2012) Bistability, bifurcations, and Waddington's epigenetic landscape. Curr Biol 22:R458-66
Ferrell Jr, James E (2011) Simple rules for complex processes: new lessons from the budding yeast cell cycle. Mol Cell 43:497-500
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
Ferrell Jr, James E (2008) Feedback regulation of opposing enzymes generates robust, all-or-none bistable responses. Curr Biol 18:R244-5
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
Hendrickson, David G; Hogan, Daniel J; Herschlag, Daniel et al. (2008) Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PLoS One 3:e2126
Santos, Silvia D M; Ferrell, James E (2008) Systems biology: On the cell cycle and its switches. Nature 454:288-9

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