Janani Ravi

Current Research Interests

• Modeling the START transition in the budding yeast cell cycle.

Deregulation of cell cycle checkpoints occurs frequently in cancer cells. Our goal here is to study the START transition in budding yeast, the transition when the cell makes a bud and commits to another round of DNA synthesis and mitosis once it reaches a size threshold. We want to understand the underlying molecular network for this size-control checkpoint. A similar checkpoint (nutritional requirement) exists for the G1/S transition in mammalian cells.

We have built a detailed mathematical model for the START transition in yeast that has been integrated with our published model of the whole cell cycle (Chen et al., 2004). Our model quantitatively explains over 50 known START mutant phenotypes. Furthermore, it addresses outstanding issues related to (i) the mechanism (and timing) of activation of the START transcription factors, SBF and MBF, (ii) the timing of export (hence inactivation) of Whi5 (SBF inhibitor), and Swi6 (a component of SBF), and (iii) size control under varying growth conditions. We are addressing ~125 more mutants pertaining to rest of the cell cycle.

• Modeling the nutritional effect on size control in budding yeast.

The size threshold for the START transition is modulated depending on the growth media--e.g. the threshold is larger in rich media like glucose (cells bud at a larger size) than in poor media like raffinose. We have built a basic model for the nutritional effect on size threshold based on the ideas of Tyers et al. 2004. They proposed that Sfp1 and Sch9, which are activators of the ribosomal protein and ribosome biogenesis regulons, are negative regulators of the START transition, as they inhibit SBF.

Our initial model (without the details of SBF and MBF regulation as described in the previous section) can explain the phenotypes of 21 START mutants. The model needs to be re-parameterized if such details are to be incorporated.

• Modeling the canoical Wnt pathway in RKO cells.

Wnt signaling plays an important role in both oncogenesis and development. Activation of the Wnt pathway results in stabilization of a transcriptional coactivator β-catenin, resulting in the activation of CycD transcription (among many other genes). In collaboration with the experimentalist Dr. Curtis Thorne in Dr. Ethan Lee's lab at Vanderbilt University, we study the pathway in RKO (human colon carcinoma) cells. These cells show bimodal distribution of β-catenin when challenged with LiCl (a drug that inhibits the pathway), indicating that a positive feedback loop exists in the signaling pathway.

We have built a simplified model based on the module of the Wnt canonical pathway by Lee et al. (2003), which contains core proteins of the β-catenin degradation machinery: GSK3β, Axin and APC. We add key regulatory interactions among these components (namely, GSK3β activates Axin, which activates GSK3β). Our model displays bistability and is in quantitative agreement with experimental results.

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