Mechanistic Analysis of a Transcriptional Switch Regulating p53 Activity and Premature Aging

2006 new Scholar Award in aging

Our lab studies the basic mechanisms of transcriptional regulationówhat turns gene expression ìon or offî in human cells. A major aspect of our work involves a protein known as p53, which works primarily by triggering changes in gene expression patterns in response to specific cellular cues. Many of the genes that p53 controls are key regulators of both cancer and aging. Activation of p53 is important for cancer prevention, whereas shutting down and controlling p53 activity is essential to prevent premature aging. The Ellison Medical Foundation is supporting work in our lab that examines a powerful biochemical switch that works to shut down active p53. This switch regulates a large protein complex known as Mediator, which works together with p53 to control expression of its target genes. Mediator is highly versatile in its biochemical function: depending upon the context, it can help activate or repress gene expression. This contrasting functionality appears to be controlled by a protein subcomplex containing 4 polypeptidesócdk8, cyclin C, Med12, and Med13óthat reversibly bind Mediator. This ìcdk8 subcomplexî can shut down activated transcription when it binds to Mediator, thus acting as a ìswitchî to control gene expression. However, the mechanisms by which this ìswitchî works are not completely defined. Using a combination of biochemical and biophysical techniques, we are working to identify the role(s) of each cdk8 subcomplex component in controlling p53 activity and Mediator function. Completion of this work will enable us to more clearly define the molecular mechanisms by which Mediator and p53 work together to control cancer and aging in humans.
Dylan J. Taatjes Ph.D.
University of Colorado - Boulder