The Andrews Lab is using functional genomics to study cell cycle transcription factor pathways and mechanisms of cell cycle regulation. In eukaryotic cells, cell division is primarily controlled in G1 phase of the cell cycle at a regulatory nexus called the restriction point or Start. Cell cycle transitions, including Start, are controlled by cyclin-dependent kinases (Cdks) whose activation requires association with regulatory subunits called cyclins. The importance of understanding Start and other cell cycle transitions is underscored by the observation that perturbations of cell cycle regulators appear to be a universal feature of cancer cells. Using a synthetic dosage suppression screen, we have produced an intriguing roster of putative kinase substrates. High through put fluorescence microscopy has also become a powerful tool in our lab to look for substrates and to map cell cycle transcription factor pathways. To this end, we are currently optimizing a screening procedure that detects changes in the steady-state levels or subcellular distribution of GFP-tagged proteins in yeast strains that harbour mutations at kinase-encoding loci. These, and other functional genomics approaches including DNA microarrays and systematic proteomics, are being applied both to specific projects in the lab and also to a larger effort to map genetic networks controlling cell cycle progression and cell polarity in yeast.

To complement these high through put  approaches we have embarked on numerous biochemical projects to dissect molecular pathways involving  genes identified in our high through put screens. For example, we are studying a family of Cdks, the Pcl-Pho85 kinases, that has emerged as an important model for the role of Cdks in broad aspects of cell regulation. Our recent studies highlight roles for Pho85 Cdks in actin cytoskeleton regulation and cell metabolism, cell cycle regulation and protein turnover. We are also exploring mechanisms of cell cycle regulation by two heterodimeric transcription factors, SBF and MBF, that coordinately control expression of a massive group of genes at Start. Studies in both yeast and mammalian cells have clearly shown that the periodic activation of transcription is a cornerstone of cell cycle regulation.  Finally, we are studying the role of Whi5 in G1 transcription initiation and also how Abp1 regulates actin cytoskeleton organization through SH3-mediated protein-protein interactions.