REGULATION OF G1-SPECIFIC GENE EXPRESSION IN YEAST

细胞增殖的适当控制是从单细胞生物到人类的所有生物系统的基础。了解细胞周期调节机制是了解人类发育和疾病的核心。 细胞周期事件的协调涉及从调节基因表达到调节蛋白质降解的调节机制的复杂相互作用。 这些机制被整合在一起，以实现一个既精确又有延展性的控制系统。 因此，细胞可以快速可靠地复制，同时对导致细胞周期组织或细胞周期进展速率改变的广泛的内部和环境影响作出反应。 调控基因表达对于细胞周期事件的正确组织至关重要。 在细胞周期中，大量重要的细胞周期功能所需的基因被周期性地转录。 其中包括细胞周期蛋白，细胞周期蛋白依赖性蛋白激酶（CDK）的基本激活剂，包括主要的细胞周期引擎。 除了周期性表达外，与CDK相关的细胞周期蛋白是细胞周期依赖性转录机制的重要调节因子。 该建议解决了在细胞周期的G1期期间特异性表达的基因的大家族的细胞周期依赖性转录的调控机制。 利用遗传学、分子生物学和生物化学方法，我们提出i）阐明G1细胞周期蛋白Cln 3对G1特异性转录激活的机制，ii）鉴定和表征G1特异性转录因子SBF和MBF的活性和调节所需的蛋白质，iii）阐明葡萄糖，大多数细胞的优选碳源，调节细胞周期调控的G1期细胞周期蛋白的表达。 我们希望这些研究将有助于我们全面了解这种基本的细胞周期控制机制及其受环境信号调节的方式。

Appropriate control of cell proliferation is fundamental to all biological systems from unicellular organisms to man. Understanding cell cycle regulatory mechanisms is central to understanding human development and disease. Coordination of cell cycle events involves a complex interplay of regulatory mechanisms ranging from regulated gene expression to regulated protein degradation. Those mechanisms are integrated to achieve a system of control that is both precise and malleable. As a consequence cells can be rapidly and reliably duplicated and at the same time be responsive to a broad range of internal and environmental influences that lead to alterations in cell cycle organization or rates of cell cycle progression. Regulated gene expression is critical for the proper organization of cell cycle events. A large number of genes required for important cell cycle functions are periodically transcribed during the cell cycle. Among them are cyclins, the essential activators of the cyclin dependent protein kinase (CDK) that comprises the primary cell cycle engine. In addition to being periodically expressed, cyclins, in association with CDKs, are important regulators of the cell cycle dependent transcriptional machinery. This proposal addresses the mechanisms governing cell cycle dependent transcription of a large family of genes that are specifically expressed during G1 phase of the cell cycle. Using genetic, molecular biological and biochemical approaches, we propose to i) elucidate the mechanism of G1-specific transcriptional activation by the G1 cyclin Cln3, ii) identify and characterize proteins required for the activity and regulation of the G1-specific transcription factors, SBF and MBF, iii) elucidate the mechanism by which glucose, the preferred carbon source of most cells, modulates cell cycle-regulated expression of G1 cyclins. We are hopeful that these studies will contribute to our overall understanding of this fundamental cell cycle control mechanism and the manner by which it is regulated by environmental signals.