Interdisciplinary Training

Michael Davis

"Cdk8 complexes in telomere maintenance and cancer"

Colon Cancer is the second leading cause of cancer-related deaths in the United States and is commonly driven by hyperactive b-catenin. Cdk8 was recently identified as an oncogene that regulates b-catenin activity and is often overexpressed in colon tumors; however, the mechanism behind Cdk8-mediated tumorigenesis remains undefined. An important step in colon cancer progression is the gain of chromosomal instability, which can be driven by telomere dysfunction. In a screen to identify genes that regulate telomere length in yeast, Cdk8 was identified as a gene whose loss lengthened telomeres; however, the mechanism by which this occurs is also unknown. Thus, in addition to Cdk8 overexpression, dysregulation of Cdk8 telomeric function may also promote tumorigenesis. Since it is unknown if Cdk8 overexpression and Cdk8 telomeric dysregulation are related, understanding the role of Cdk8 in each of these oncogenic processes will help us better define the underlying causes of colon cancer. Therefore, the goal of this proposal is to differentiate these two Cdk8 functions: one that regulates telomere maintenance and another that promotes tumorigenesis through overexpression. To address this goal, I will utilize a cross-organismal, interdisciplinary approach that employs the power of yeast genetic analysis and human cell culture models, and this work address fundamental questions important to cell and tumor biology.