MSc Candidate, Aristizabal Lab Understanding the regulation and function of Cdk8 Cdk8 is a conserved protein kinase and a member of the Mediator transcription co-activator complex. Accumulating evidence highlights Cdk8 as a crucial oncogene in colorectal cancer, emphasizing the need to understand its function and regulation. Notably, CDK8 is amplified or overexpressed in approximately 60% of colon cancer tumors, and elevated CDK8 levels correlate with tumor stage and reduced patient survival. Supporting its oncogenic role, knockdown of CDK8 diminishes the proliferation of colon cancer cell lines, while overexpression induces tumor formation in immunodeficient mice, effects that depend upon Cdk8's kinase activity. Beyond colorectal cancer, growing research also implicates CDK8 in melanoma, leukemia, as well as breast, pancreatic, and prostate cancer, evidence that has stimulated the development of Cdk8 inhibitors for cancer therapy. Despite a growing interest to target Cdk8 for anti-cancer treatment we have limited information about Cdk8 regulation, a knowledge gap that may complicate efforts to block its activity. For my exit seminar, I will discuss my work using the budding yeast model system to understand the function and regulation of Cdk8 by leveraging disease-associated variability and recent insight from structural and biochemical analyses. Specifically, I have leveraged data from The Cancer Genome Atlas and ClinVar to identify CDK8 missense mutations that are likely to affect function. This work led me to find a cluster of mutations that localize to the kinase ATP binding pocket or sites of interaction with CycC and Med12, proteins known to regulate Cdk8 kinase activity. My findings so far suggest that most of the mutants disrupt Cdk8 function, resulting in a feedback mechanism that leads to an increase in Cdk8 protein and mRNA levels. In addition, my work examining the role of Med12 in regulating Cdk8’s activity in vivo showed that this interaction contributes to Cdk8 function in a condition specific manner. Collectively, this research sheds light on the function and regulation of Cdk8, work that will inform the development of targeted therapies and enhance our understanding of the mechanisms by which Cdk8 contributes to cancer development.
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