The International Journal of Biochemistry & Cell Biology
ReviewCoordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway
Section snippets
Endoplasmic reticulum stress
In eukaryotic cells, the endoplasmic reticulum (ER) is the first organelle in the secretory pathway. As such, the ER serves as a site of secretory protein synthesis and modification prior to directing protein delivery to other secretory organelles. This process is highly regulated, consisting of chaperones, signaling molecules and a network of degradation machinery that maintain homeostasis (Schroder & Kaufman, 2005). Upon disruption in either protein folding or modification within the ER, a
The unfolded protein response
In mammalian cells, the proximal signaling events that occur in response to UPR activation involve the release of ER-resident signaling molecules, activating transcription factor 6 (ATF6), inositol requiring 1 (Ire1) and PKR-like endoplasmic reticulum kinase (PERK), from binding to the ER-resident chaperone, BIP/GRP78 resulting in their subsequent activation (Bertolotti, Zhang, Hendershot, Harding, & Ron, 2000; Haze, Yoshida, Yanagi, Yura, & Mori, 1999; Li et al., 2000, Ma et al., 2002a). As a
Oxidative stress
While the induction of the UPR results from stress emanating from one organelle, the broad response termed oxidative stress results from the coordination of hundreds of signaling molecules that reside in all cellular compartments (Hayes & Pulford, 1995). On a broad scale, oxidative stress results from the exposure of cells to ROS (Richter et al., 1995, Rushmore et al., 1991). ROS may originate during cellular metabolic processes such as oxidative phosphorylation within the mitochondria, or they
Nrf2/Keap1 signaling pathway
Nrf2 belongs to the Cap ‘n’ Collar (CNC) family of basic leucine zipper (bZip) transcription factors that includes NF-E2, Nrf1-3 and Bach1-2 (Andrews, Erdjument-Bromage, Davidson, Tempst, & Orkin, 1993; Chan, Han, & Kan, 1993; Kobayashi et al., 1999, Moi et al., 1994; Oyake et al., 1996). While NF-E2 is restricted to erythrocytes where it regulates globin-specific gene expression (Andrews et al., 1993), the related NF-E2 related factor (Nrf) proteins (Nrf1-3) are ubiquitously expressed and
Neurodegenerative diseases
The broad classification of neurodegenerative disorders encompasses a group of devastating diseases characterized by abnormal neuronal physiology coupled with a loss of neurological function. While the causative effects of this family of diseases are still being investigated, it is clear that alterations in protein folding and redox homeostasis are prominent features of the diseases (Andersen, 2004, Forman et al., 2003). Animal models and human autopsy results consistently reveal the
Outlook
A large body of work has established paradigms for both UPR and oxidative stress signaling, including mechanisms of regulation and modes of activity. We are just now beginning to appreciate the vast potential for these pathways in development and homeostatic control as well as disease prevention and progression. While the connection between ER stress and the subsequent induction of oxidative stress has been appreciated for several years, recent data have offered a mechanism for the intersection
Acknowledgments
We thank members of our laboratory for helpful discussions and support from NIH/NCI CA104838 (JAD).
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