- Jun-yuan Ji
- Associate Professor
- Room 233 Reynolds Medical Building
Our laboratory is interested in cell cycle and transcriptional regulation during development and tumorigenesis. Using Drosophila and cultured human cancer cell lines as model systems, we combine genetic, cell biological, and biochemical approaches to elucidate the molecular and genetic regulatory circuits that control cell proliferation and gene expression. Specifically, our major focus is to study the functions and regulation of Cyclin-dependent kinase 8 (CDK8). By performing genetic screens using Drosophila, we identified CDK8 as a potent inhibitor of E2F1, which is a key transcription factor that regulates the G1 to S-phase transition. In both Drosophila and human cancer cells, we observed that CDK8 inhibits E2F1-dependent transcription by directly binding to and phosphorylating E2F1, which may turn off the re-initiation of E2F1-mediated transcription. Interestingly, CDK8 is recently identified as an oncoprotein in melanoma and colorectal cancer. The genes encoding CDK8 and its regulatory partner Cyclin C (CCNC) are frequently amplified or mutated in a variety of human cancers. Importantly, inhibiting CDK8 potently blocks the growth of colorectal cancer cells that harbor CDK8 amplification, suggesting that CDK8 kinase is a promising drug target. Therefore, it is important to understand the regulatory network, including both upstream regulators and downstream effectors, of CDK8-Cyclin C (CycC) in both normal development and tumorigenesis.
Recently, we have identified CDK8 and CycC as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes and mouse livers. The inhibitory effect of CDK8 and CycC on de novo lipogenesis is through CDK8 phosphorylation of the SREBP-1c transcription factor at a conserved threonine residue. Consistent with the physiologic regulation of lipid biosynthesis, the levels of CDK8 and CycC proteins are reduced by feeding and insulin. Taken together, these results suggest a novel and conserved role of CDK8 and CycC in regulating lipid homeostasis. Dysregulated transcription of key lipogenic enzymes has been observed in a variety of human cancers as well as diseases and conditions collectively known as metabolic syndrome. Further analyses of CDK8 functions and regulation may provide important insights to better understand how dysregulation of CDK8-CycC contributes tumorigenesis and other diseases.