The long-term goal of this work is to understand how cells sense and respond to extracellular signals. We will study a signal transduction cascade in budding yeast important for responding to changes in the level of extracellular inorganic phosphate (the """"""""Pho"""""""" pathway). We have previously shown that the transcription factor Pho4 is a target for a phosphate-responsive signal transduction pathway composed of the Pho80-Pho85 cyclin-cyclin dependent kinase (CDK) complex and the CDK inhibitor Pho81. We understand much about the function and regulation of these components, but little about how cells sense phosphate levels and generate an appropriate physiological response. We will focus on how the Pho pathway processes information and coordinates a response to different phosphate levels. The CDK Pho85 associates with nine cyclins, in addition to the cyclin Pho80 involved in phosphate metabolism. The processes regulated by these Pho85-cyclin complexes are unclear, largely because few physiologically-relevant substrates have been identified. We will employ a new method for identification of protein kinase substrates, with the goal of providing insight into the biological processes regulated by the CDK Pho85. Ultimately the phosphate signal reaches the nucleus, resulting in regulation of phosphate-responsive genes such as PH05. The promoter of the PH05 gene is an excellent system for studying the relationship between gene regulation and chromatin structure. We have recently identified factors which are required to remodel PH05 promoter chromatin and have observed that small molecules (inositol polyphosphates) regulate this process. We will focus on understanding how chromatin is remodeled at the PH05 promoter and how this process is regulated. These studies will provide insight into mechanisms of signal transduction and transcriptional regulation, basic cell biological processes which are misregulated in human diseases and cancer.
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