Thomas Weber
Pacific Northwest National Laboratory, USA
Title: Aberrant regulation of oscillatory behavior in the extracellular signal regulated kinase (ERK) pathway: A toxicologists’ perspective?
Biography
Biography: Thomas Weber
Abstract
Oscillatory behavior occurs in pathways central to toxicological responses, including ERK, NF-κB, p53-MDM2 and Ca2+, however, the specific biological information encoded by oscillations is incompletely understood. We are the first to demonstrate that ERK oscillations regulate unique gene expression patterns in multiple experimental model systems, indicating that transcriptional regulation is one output for oscillatory behavior. We will discuss our most advanced experimental human model system that highlights a linkage between ERK oscillations and a transcriptional co-activator (MED1) whose half-life and activity is directly regulated by ERK-dependent phosphorylation as a feasible mechanism. Several toxicants (oxygen free radicals, ionizing radiation, bromate) inhibit ERK oscillations, and exploit well established stress-responsive signaling pathways (e.g. p38) to inhibit ERK signaling. However, the ERK feedback control processes specifically regulated by the stress response are undefined. We will also discuss experimental evidence that the inappropriate regulation of negative feedback loops in the ERK pathway can result in aberrant activation of ERK signaling, a response that has received little attention in a toxicological context. Finally, we have observed negative selection of ERK oscillations in vitro which may be important in view of the increased emphasis placed on in vitro screening assays in toxicology. Transcriptional misregulation is a mechanism frequently associated with toxic outcomes, therefore, the aberrant regulation of ERK oscillations by toxicants warrants further consideration in view of the unique gene expression profiles associated with this dynamic signaling behavior.