Role of RGS2 in the Integrated Stress Response

点击翻译按钮获取中文摘要

When a cell becomes sick or damaged, its metabolism is altered in various ways to promote recovery and survival. If recovery is not possible or will lead to it becoming abnormal, however, the unhealthy cell will self-destruct through a process known as apoptosis. Either way, the reaction of an individual cell to damage generally promotes the long-term viability of the living organism that it belongs to. In the cell, both pro-survival and pro-apoptosis reactions arise from a coordinated program of changes referred to as the Integrated Stress Response. These various changes may be beneficial, destructive, or both, and how they balance out to allow the cell to continue living or alternatively bring about its death is not well understood. ******The proposed studies focus on a protein called RGS2 (regulator of G protein signaling 2), which we and others have shown to be increased in response to cellular damage caused by chemical or physical insults. The specific role of RGS2 in the Integrated Stress Response is unknown, although our findings to date suggest that it may contribute to both cell recovery and apoptosis. We previously reported that RGS2 binds to the cellular protein synthesis machinery, which decreases the overall rate of protein synthesis and thereby spares cellular resources that can be redirected towards survival. More recently, we have uncovered evidence that the latter effect is accompanied by RGS2-induced increases in the stress proteins ATF4 (activating transcription factor 4) and CHOP (C/EBP homologous protein). ATF4 and CHOP both are among an increasingly recognized group of proteins that are selectively made during times of stress, and they in turn can trigger multiple survival and apoptotic biochemical cascades. We hypothesize that RGS2 can additionally promote the synthesis of other such stress proteins, and that on balance these changes will lead to either cell survival or apoptosis, depending upon the cell type as well as the nature and the severity of the stress encountered. Overall, the experiments outlined in this Discovery Grant application will further our general understanding of how cells respond to stress and also elucidate the specific functions of RGS2 in this process.