Regulation of cell differentiation by RNA Polymerase II-associated Cdk8

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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.