Coupling Endoplasmic Reticulum Stress to the Cell Death Program

By Rammohan V. Rao, E. Hermel, S. Castro-Obregón, G. Del Rio, Lisa M. Ellerby, H. Ellerby, Dale E. Bredesen. Journal of Biological Chemistry, 2001

828 citations recorded by the source corpus.

The endoplasmic reticulum (ER) is the site of assembly of polypeptide chains destined for secretion or routing into various subcellular compartments. It also regulates cellular responses to stress and intracellular Ca2+ levels. A variety of toxic insults can result in ER stress that ultimately leads to apoptosis. Apoptosis is initiated by the activation of members of the caspase family and serves as a central mechanism in the cell death process. The present study was carried out to determine the role of caspases in triggering ER stress-induced cell death. Treatment of cells with ER stress inducers such as brefeldin-A or thapsigargin induces the expression of caspase-12 protein and also leads to translocation of cytosolic caspase-7 to the ER surface. Caspase-12, like most other members of the caspase family, requires cleavage of the prodomain to activate its proapoptotic form. Caspase-7 associates with caspase-12 and cleaves the prodomain to generate active caspase-12, resulting in increased cell death. We propose that any cellular insult that causes prolonged ER stress may induce apoptosis through caspase-7-mediated caspase-12 activation. The data underscore the involvement of ER and caspases associated with it in the ER stress-induced apoptotic process.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a8488dea3d0919f0beef97fc95b029c7452a0ccf

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In Cell Biology

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2. D. Ron
3. J. Malhotra
4. Junying Yuan
5. M. Boyce
6. D. Rutkowski
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8. E. White

In Epidemiology

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In Molecular Biology

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2. Junying Yuan
3. D. Ron
4. D. Rutkowski
5. M. Boyce
6. Jun Wu
7. E. White
8. R. Amaravadi

Citations in the corpus

• β-Cell death during progression to diabetes (2001, background): “Also involved in this pathway are IRE-1, TRAF-2, calpain, caspase-7 and perhaps caspase-9 (ref”
• A decade of caspases (2003, background): “One possible explanation is that executioner caspases may have distinct roles in specific pathways, such as ER stress for caspase-7 (Rao et al., 2001), but have redundant functions in the majority of the general apoptotic events and thus, abolition of all three may be required to observe complete…”
• Regulation of apoptosis by endoplasmic reticulum pathways (2003, background): “In spite of this discovery, two reports showed that antibodies against murine caspase-12 detect an appropriately sized protein in human cells that is processed following ER stress (Nakagawa et al., 2000; Rao et al., 2001).”
• Initiation and execution of lipotoxic ER stress in pancreatic β-cells (2008, methodology): “For β-cell isolation, islets were dispersed and β-cells purified by autofluorescence-activated cell sorting (FACS; FACStar, Becton Dickinson and Co., Sunnyvale, CA) (Pipeleers et al., 1985; Rasschaert et al., 2005).”
• Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium (2007, neutral): “be an increase in the capacity of the ER folding machinery, reduction of the amount of proteins entering the ER, enhanced clearance of the proteins from the ER, apoptosis or autophagy.(16,18,19,33) PERK, IRE1 and increased [Ca2þ ]C have been implicated as mediators of ER stress-induced autophagy in ”
• Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease (2010, neutral): “CHOP is induced through the PERK pathway, caspase-12 and JNK signaling are activated, and proapoptotic Bcl-2 proteins BAX and BAK are switched on by the IRE1a pathway (Hetz et al., 2006; Rao et al., 2004).”
• Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins (2006, background): “, [50,51]), and indeed, prolonged and severe pharmacological perturbation of ER function in cultured cells does indeed lead to death(e.”
• Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. (2007, background): “However, if the stress is too severe or lasts for too long, decompensation of ER function could induce cell death.(5) Macroautophagy (referred as autophagy hereafter) is another major intracellular degradation system.”
• ER stress and neurodegenerative diseases (2006, background): “Bcl-2 family proteins play a crucial role in ER–mitochondria interactions, and Bcl-2 and Bcl-xL associate with mitochondria and with the ER membrane.(2,3) Bcl-2 in conjunction with Bax”