| Description |
As the entry point for the secretory pathway, the endoplasmic reticulum (ER) is responsible for folding and processing secreted proteins. ER stress occurs when the folding capacity of the ER is exceeded by incoming proteins, thus resulting in an accumulation of potentially harmful misfolded proteins. This condition activates the unfolded protein response (UPR). The UPR consists of three independent signaling branches that alleviate ER stress by altering gene expression to decrease the incoming protein load while simultaneously increasing the folding capacity of the ER. During chemically induced ER stress, there is strong increase in the abundance of the mRNA coding for the mammalian transcription factor hairy and enhancer of split 1 (Hes1). Since Hes1 plays critical roles in development and cancer, the goal of this thesis was to determine the mechanism behind the increase in Hes1 mRNA, discover the protein's downstream targets during ER stress, and determine the overall consequences for the cell. Here we show that Hes1 greatly increases cellular viability during conditions of ER stress. We also show that regulation of Hes1 during ER stress in mammalian cells is dependent on the UPR factor Perk. Furthermore, this regulation is due to a dramatic increase in the stability of the mRNA. Previous work in D. melanogaster shows that Hairy represses Idh genes during hypoxia-induced ER stress. Interestingly, we find that Hes1 is responsible for suppressing the synthesis of Idh3? mRNA during ER stress. Additional work is required to determine the full consequences of this regulation of Idh3? as well as identifying other targets for Hes1. |
