Regulation of endoplasmic reticulum stress induced apoptosis by eIF2α phosphatases
Faculty Mentor Name
Douglas C. Weiser
Research or Creativity Area
Natural Sciences
Abstract
The Unfolded Protein Response (UPR) is a complex transcriptional and translational pathway that responds to the accumulation of unfolded proteins in the endoplasmic reticulum (ER-stress). One branch of the UPR involves phosphorylation of eukaryotic translation initiation factor 2 (eIF2α) by to attenuate global protein translation and reduce the accumulation of proteins in the secretory pathway. This pathway is multifunctional and can be both protective, allowing for recovery from ER stress, or promote ER-stress induced apoptosis. Two scaffolding proteins, GADD34 and CReP, bind to Protein Phosphatase 1 and promote the dephosphorylation of eIF2α. We use zebrafish as a model for GADD34 and CReP function and to understand their role in ER stress induced apoptosis. Using whole mount in situ hybridization we analyzed in stress-induced expression of pro-survival genes such as Bip and apoptotic genes such as Chop in both wild-type zebrafish embryos and mutant embryos lacking GADD34 and CReP. We believe this system will provide an ideal model elucidate the mechanism of action of GADD34 and CReP and lead to a better understanding of ER-stress induced apoptosis.
Regulation of endoplasmic reticulum stress induced apoptosis by eIF2α phosphatases
The Unfolded Protein Response (UPR) is a complex transcriptional and translational pathway that responds to the accumulation of unfolded proteins in the endoplasmic reticulum (ER-stress). One branch of the UPR involves phosphorylation of eukaryotic translation initiation factor 2 (eIF2α) by to attenuate global protein translation and reduce the accumulation of proteins in the secretory pathway. This pathway is multifunctional and can be both protective, allowing for recovery from ER stress, or promote ER-stress induced apoptosis. Two scaffolding proteins, GADD34 and CReP, bind to Protein Phosphatase 1 and promote the dephosphorylation of eIF2α. We use zebrafish as a model for GADD34 and CReP function and to understand their role in ER stress induced apoptosis. Using whole mount in situ hybridization we analyzed in stress-induced expression of pro-survival genes such as Bip and apoptotic genes such as Chop in both wild-type zebrafish embryos and mutant embryos lacking GADD34 and CReP. We believe this system will provide an ideal model elucidate the mechanism of action of GADD34 and CReP and lead to a better understanding of ER-stress induced apoptosis.
