GENETIC ANALYSYS OF THE IN VIVO FUNCTION AND REGULATION OF THE ONCOPROTEIN CDK8 IN DROSOPHILA

Abstract

Cyclin-Dependent Kinase 8 (CDK8) has recently emerged as an oncoprotein that is amplified in both colorectal and melanoma cancers. The importance of CDK8 and its regulatory partner Cyclin C (CycC) is highlighted by the clinical observations showing that CDK8 and CycC are frequently amplified, mutated, or deleted in a variety of human cancers (4). Inhibiting CDK8 potently blocks the growth of colorectal cancer cells that harbor CDK8 amplification, suggesting that CDK8 is a promising drug target. Accordingly, several pharmaceutical companies are tremendously interested in developing CDK8-specific inhibitors (5). However, for such drugs to be successful, it is essential to understand the regulatory network of CDK8-CycC including both the upstream regulators and the downstream effectors in normal development and tumorigenesis. To date, little is known about how CDK8-CycC activity is regulated. In addition, the downstream targets and the biological functions of CDK8 in metazoans remain poorly understood.

Importantly, both CDK8 and CycC are highly conserved in all eukaryotes. Thus we use Drosophila as an experimental system to identify both the upstream regulators and downstream effectors of CDK8. We expect to elucidate the fundamental roles of CDK8- CycC and thereby gain insight of how their deregulations contribute to various cancers. Because cdk8 or cycC homozygous mutants are lethal in the pupal stage, we set out to vary CDK8 and CycC in a tissue-specific manner by using the Gal4-UAS system. Importantly, certain phenotypes can be modified by second-site mutations, which provide us with a unique opportunity to genetically dissect the functions and regulation of CDK8-CycC in vivo.