Regulation of cell differentiation by RNA Polymerase II-associated Cdk8

细胞的生长和分化受到来自环境的信号的高度调节。 芽殖酵母Saccharomyces cerevisiae为研究细胞分化的分子细节提供了一个重要的模型，细胞分化是如何通过环境信号调节转录因子来控制的。 在营养限制的条件下，酵母从它们的正常球形分化成细长的丝状假菌丝细胞形态，其能够钻入生长基质以促进锻造营养。 我们的研究表明，Cdk 8，一种与RNA聚合酶II介体相关的细胞周期蛋白依赖性蛋白激酶，在控制细胞分化的决定中起着关键作用。 Cdk8磷酸化并抑制至少两种序列特异性DNA结合蛋白，包括Ste 12和Phd 1，它们负责细胞分化所需基因的激活。 当细胞遇到不利的营养条件时，典型的是氮或碳来源不足，Cdk 8活性受到抑制，这反过来又减轻了Cdk 8对这些因子的负面影响，从而使驱动分化的基因超活化。 这些结果确定Cdk8作为控制细胞分化的信号的主要目标，我们的目标是确定营养信号控制Cdk8功能的分子机制，并表征其控制分化的靶底物蛋白的完整谱。

Cellular growth and differentiation are highly regulated by signals from the environment. The budding yeast Saccharomyces cerevisiae has provided an important model to study molecular details of how cellular differentiation is controlled through regulation of transcription factors by signals from the environment. Under conditions of nutrient limitation, yeast differentiate from their normal spherical shape into an elongated filamentous pseudohyphal cellular morphology, which are capable of burrowing into the growth substrate to facilitate forging for nutrients. Our research has shown that Cdk8, a cyclin-dependent protein kinase associated with the RNA Polymerase II mediator, plays a critical role in controlling the decision to undergo cellular differentiation. Cdk8 phosphatorylates and inhibits at least two sequence-specific DNA binding proteins, including Ste12 and Phd1, which are responsible for activation of genes necessary for cellular differentiation. When cells encounter unfavorable nutrient conditions, typified by poor sources of nitrogen or carbon, Cdk8 activity is inhibited, which in turn relieves the negative effect of Cdk8 on these factors to allow hyperactivation of genes that drive differentiation. These results identify Cdk8 as a primary target for signals controlling cellular differentiation, and our objectives are to determine the molecular mechanisms by which nutrient signals control Cdk8 function, and to characterize the complete spectrum of its target substrate proteins for controlling differentiation.