REGULATION OF G1-SPECIFIC GENE EXPRESSION IN YEAST

从单细胞生物到人类，对细胞增殖的适当控制是所有生物系统的基础。理解细胞周期调控机制是理解人类发育和疾病的核心。细胞周期事件的协调涉及从调控基因表达到调控蛋白质降解的调控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具有延展性的控制系统。因此，细胞可以快速可靠地复制，同时对广泛的内部和环境影响作出反应，这些影响导致细胞周期组织或细胞周期进展速度的改变。调控基因表达对细胞周期事件的正确组织至关重要。在细胞周期中，大量重要细胞周期功能所需的基因是周期性转录的。其中包括细胞周期蛋白，它是细胞周期蛋白依赖性蛋白激酶（CDK）的基本激活因子，CDK是细胞周期的初级引擎。除了周期性表达外，细胞周期蛋白与CDKs结合，是细胞周期依赖性转录机制的重要调节因子。这一建议解决了在细胞周期G1期特异性表达的一大家族基因的细胞周期依赖转录的调控机制。利用遗传、分子生物学和生物化学的方法，我们建议i)阐明G1周期蛋白Cln3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的活性和调控所需的蛋白质，iii)阐明葡萄糖（大多数细胞的首选碳源）调节细胞周期调节的G1周期蛋白表达的机制。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.