Effects of Radiation on Proteasome Function in Prostate Cancer Cells.

摘要

The proteasome is involved in the progression of the cell cycle and its degrading activity controls the lifetime of most cellular proteins, including many regulatory proteins. This multicatalytic complex is also the main target of many cancer therapies, including radiation, and our lab has already extensively shown data on radiation-induced proteasome inhibition. Based on the observation that radiation causes chemical modifications to many proteins and/or enzymes present in a cell through free radicals production, we hypothesized that irradiation induces structural, other than functional changes within the 26S subunits and proteins interacting with it. These conformational changes are the ones that eventually affect its activity, thus its capacity of degrading proteins. As a cell progresses through the cell cycle-specific proteins need to be degraded in order for the cell to proceed to the next phase. So far, the activity of the 26S proteasome was thought to be constant throughout the different phases of the cell cycle, and that the degradation of specific proteins was only dependent on their ubiquitination and not by the activity levels of the proteasome itself. Our hypothesis is that there is another level of regulation that happens as the cell progresses through the cell cycle. This level is mediated by regulating the degradation efficiency of the proteasome itself. If this were in fact true, than cells would dynamically change the state of the proteasome through the cell cycle, which could explain why radiation can only partially inhibit proteasome function if the susceptibility of the proteasome to radiation changes with its regulation.