Research Interests

In early work, I used genetic analysis in yeast to study transcriptional regulation in response to glucose deprivation. I isolated sucrose-nonfermenting (snf) mutants that were unable to express the glucose-repressed SUC2 gene. Analysis of these mutants led us to identify subunits of SNF1 protein kinase and the SWI/SNF chromatin-remodeling complex, which proved to have broad roles in transcriptional control. Our finding that the SNF1 gene encodes a protein kinase catalytic subunit showed that protein phosphorylation is required for release of glucose repression, and we went on to study mechanisms by which SNF1 controls transcription of metabolic genes. We also showed that SNF1 protein kinase is a heterotrimer with alternate noncatalytic subunits, and we characterized interactions among the subunits and their roles in regulating catalytic activity and subcellular localization. We discovered three protein kinases that phosphorylate the catalytic subunit and activate SNF1. SNF1 is highly conserved, and its human ortholog is AMP-activated protein kinase (AMPK), which similarly has a central role in metabolic regulation. The identification of yeast kinases that activate SNF1 allowed us to identify the related human kinase LKB1, a tumor suppressor, as the first activating kinase of AMPK.

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Section 26: Genetics