The GAL genes of bakers' yeast (S. cerevisae) provide a familiar and well-characterized model for mechanisms of eukaryotic gene regulation. Expression of thise genes is regulated in two ways: it is induced by galactose, and repressed by glucose. The basis for induction by galactose is well-understood, involving both positively (GAL4) and negatively-acting (GAL80) proteins. Glucose repression is less well understood. It iperates upon the GAL genes through several mehanisms: 1) it reduces the level of the inducer derived from galactose; 2) it represses expression of GAL4, which encodes the transcriptional activator; 3) it directly inhibits transcription through URS sequences in the GAL gene promoters. Glucose repression can be viewed as a signal transduction mechanism, whereby the addition of glucose generates a signal that ultimately affects function of gene regulatory proteins. Our long-term goals are to understand the nature of the signal, how it is generated from glucose, and how it eventually effects gene expression. We believe this will provide fundamental knowledge relevant to growth control of more complex organisms. Tumorigenesis is due to uncontrolled cell growth, which in many cases is caused by altered gene expression. In addition, since glucose is a key nutrient for most cells, the ability to sense its availability is critical for controlling growth.
The specific aims are: >To elucidate mechanisms of glucose repression.
This aim will account for the majority of our efforts, and can be divided into three projects. First, we wish to understand how GAL4 transcription is repressed by glucose. Second, we intend to explain the mechanisms that inhibit transcription directly through the URS elements in the GAL1 promoter. Third, we hope to learn how the signal for glucose repression is produced by identifying and analyzing genes that might be involved in signal generation. >To identify genes required for glucose-induced gene expression. It seems possible that some of the components of mechanisms of glucose induction and glucose repression of gene expression might be shared. To reveal such components, we hope to identify and analyze genes required for regulation of both types of genes. Such genes could be involved in signal generation. >To learn more about how GAL4 protein activates transcription. A few specific experiments are proposed to 1) learn how GAL4 protein recognizes its DNA binding site, and 2) to identify proteins it interacts with to activate transcription. >To analyze the GAL4 promoter. This promoter is among the weakest in yeasts. We believe if we can understand why the GAL4 promoter is weak, we will learn something important abour mechanisms of transcriptional activation. In addition, we wish to identify the transcriptional activators of GAL4, because we believe thay are likely to be important transcription factors in yeasts.
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