Regulation of Yeast PHO5 Gene

描述（由申请人提供）：这项工作的长期目标是了解细胞如何感知和响应营养可用性的变化。我们将研究出芽酵母中响应细胞外无机磷酸盐水平变化的重要信号转导级联（Pho途径）。转录因子Pho4是由Pho80-Pho85 cyclin-cyclin依赖性激酶（CDK）复合物和CDK抑制剂Pho81组成的磷酸盐应答信号转导通路的靶标。虽然我们对Pho80-Pho85下游信号传导的机制方面了解很多，但我们对磷酸盐可用性的变化如何传达给该激酶，从而导致其活性的调节知之甚少。最近，我们令人惊讶地发现，在所有真核细胞中发现的代谢物myo-D-inositol heptakisphosphate (IP7)，通过控制CDK抑制剂Pho81抑制Pho80-Pho85的能力，将磷酸盐可用性的变化与Pho途径活性的变化联系起来。IP7水平响应磷酸盐限制而增加，并触发pho81依赖性的Pho80-Pho85抑制。这一观察结果为研究这种进化上保守的信号分子的功能和揭示细胞感知磷酸盐可用性变化的机制提供了一个独特的机会。在接下来的工作中，我们将研究IP7调控Pho80-Pho85-Pho81周期蛋白- cdk - cdk抑制剂复合物活性的机制，确定磷酸盐可用性的变化如何导致IP7水平的变化，并确定参与肌醇多磷酸代谢和磷酸盐信号传导的新基因和代谢物。这项工作将大大促进我们对信号转导机制的理解，并为细胞如何监测营养水平、人类疾病和癌症中被错误调节的基本过程提供见解。

DESCRIPTION (provided by applicant): The long-term goal of this work is to understand how cells sense and respond to changes in nutrient availability. 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). 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. Although we know much about the mechanistic aspects of signaling downstream of Pho80-Pho85, we know little about how changes in phosphate availability are communicated to this kinase, resulting in regulation of its activity. Recently, we made the surprising finding that a metabolite found in all eukaryotic cells, myo-D-inositol heptakisphosphate (IP7), links changes in phosphate availability to changes in the activity of the Pho pathway by controlling the ability of the CDK inhibitor Pho81 to inhibit Pho80-Pho85. IP7 levels increase in response to phosphate limitation and trigger Pho81-dependent inhibition of Pho80-Pho85. This observation provides a unique opportunity to investigate the function of this evolutionarily conserved signaling molecule and to unravel the mechanism by which cells sense changes in phosphate availability. In proposed work, we will investigate the mechanism by which IP7 regulates the activity of the Pho80-Pho85-Pho81 cyclin-CDK-CDK inhibitor complex, determine how changes in phosphate availability lead to changes in IP7 levels, and identify new genes and metabolites involved in inositol polyphosphate metabolism and phosphate signaling. This work will substantially advance our understanding of the mechanisms of signal transduction and provide insights into how cells monitor nutrient levels, basic processes that are misregulated in human diseases and cancer.