Cellular Stress Responses: Cell Survival and Cell Death

Cells can respond to stress in various ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective or destructive stress response depends to a large extent on the nature and duration of the stress as well as the cell type. Also, there is often the interplay between these responses that ultimately determines the fate of the stressed cell. The mechanism by which a cell dies (i.e., apoptosis, necrosis, pyroptosis, or autophagic cell death) depends on various exogenous factors as well as the cell's ability to handle the stress to which it is exposed. The implications of cellular stress responses to human physiology and diseases are manifold and will be discussed in this review in the context of some major world health issues such as diabetes, Parkinson's disease, myocardial infarction, and cancer

Inhibition by Anandamide of 6-Hydroxydopamine-Induced Cell Death in PC12 Cells

6-hydroxydopamine (6-OHDA) is a selective neurotoxin that is widely used to investigate cell death and protective strategies in models of Parkinson's disease. Here, we investigated the effects of the endogenous cannabinoid, anandamide, on 6-OHDA-induced toxicity in rat adrenal phaeochromocytoma PC12 cells. Morphological analysis and caspase-3 activity assay revealed that anandamide inhibited 6-OHDA-induced apoptosis. The protection was not affected by antagonists of either cannabinoid receptors (CB1 or CB2) or the vanilloid receptor TRPV1. Anandamide-dependent protection was reduced by pretreatment with LY294002 (inhibitor of phosphatidylinositol 3-kinase, PI3K) and unaffected by U0126 (inhibitor of extracellularly-regulated kinase). Interestingly, phosphorylation of c-Jun-NH2-terminal kinase (JNK) in cells exposed to 6-OHDA was strongly reduced by anandamide pre-treatment. Furthermore, 6-OHDA induced c-Jun activation and increased Bim expression, both of which were inhibited by anandamide. Together, these data demonstrate antiapoptotic effects of anandamide and also suggest a role for activation of PI3K and inhibition of JNK signalling in anandamide-mediated protection against 6-OHDA

Cell Stress and Cell Death

Editorial: This special issue on Cell Stress and Cell Death is aimed at bringing together recent developments in the fields of cellular stress and cell death and, in particular, the interplay between cell stress responses and cell death. The special issue opens with a review by S. Fulda et al. which provides an overview of how cells can respond to stress in a variety of ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective response or succumb to death depends to a large extent on the nature and duration of the stress as well as the cell type. For example, milder stresses can lead to protection through activation of the heat shock response or the unfolded protein response (UPR). This review also describes several types of cell death (e.g., apoptosis, necrosis, pyroptosis, or autophagic cell death) and the mechanism by which a cell dies often depends on various exogenous factors as well as the cell’s ability to handle the stress to which it is exposed. The implications of cellular stress responses for human physiology and disease are multifold and are discussed in this review in the context of some major world health issues such as diabetes, Parkinson’s disease, myocardial infarction, and cancer. ..

Editorial: Cell stress and cell death

金沢大学医薬保健研究域医学

HSPB1 facilitates ERK-mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress-induced apoptosis

BIM, a pro-apoptotic BH3-only protein, is a key regulator of the intrinsic (or mitochondrial) apoptosis pathway. Here, we show that BIM induction by endoplasmic reticulum (ER) stress is suppressed in rat PC12 cells overexpressing heat shock protein B1 (HSPB1 or HSP27) and that this is due to enhanced proteasomal degradation of BIM. HSPB1 and BIM form a complex that immunoprecipitates with p-ERK1/2. We found that HSPB1-mediated proteasomal degradation of BIM is dependent on MEK-ERK signaling. Other studies have shown that several missense mutations in HSPB1 cause the peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, which is associated with nerve degeneration. Here we show that cells overexpressing CMT-related HSPB1 mutants exhibited increased susceptibility to ER stress-induced cell death and high levels of BIM. These findings identify a novel function for HSPB1 as a negative regulator of BIM protein stability leading to protection against ER stress-induced apoptosis, a function that is absent in CMT-associated HSPB1 mutants

Inhibition of IRE1 alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1 beta

The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPS). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1 beta into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1 alpha, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1 alpha RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1 beta processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1 alpha signaling in conditions of excessive inflammasome formation

Antioxidant-mediated inhibition of the heat shock response leads to apoptosis

AbstractWe examined the hypothesis that reactive oxygen species (ROS) contribute to the induction of heat shock proteins (hsps) during stress response. Exposure of HL-60 human myelocytic cells to 42°C induced both hsp72 and hsp27. In the presence of the antioxidant molecules pyrrolidine dithiocarbamate or 1,10-phenanthroline induction of hsp72 and 27 was significantly decreased, while N-acetyl-l-cysteine caused a slight reduction. Prevention of hsp induction was associated with heat sensitization and increased caspase activity, indicating that the cells were undergoing apoptosis. These data suggest that ROS contribute to the induction of hsps and furthermore, that hsp induction and apoptosis are mutually exclusive events within the same cell

How physicians perceive and utilize information from a teratogen information service: The Motherisk Program

BACKGROUND: Teratogen information services have been developed around the world to disseminate information regarding the safety of maternal exposures during pregnancy. The Motherisk Program in Toronto, Canada, fields thousands of these inquiries per year. Our primary objective was to evaluate the perception and utilization of information received from us by physicians. Our secondary objective was to examine their information seeking behavior, in particular regarding teratogen information. METHODS: A one page survey was sent to physicians who had called Motherisk for information concerning pregnancy exposures in the previous 30 days for three months. Among the questions that were asked were demographics, which included gender, years in practice, specialty, information resources, and how they utilized the information received from Motherisk. RESULTS: We received 118/200 completed questionnaires (59% response rate). The mean age of the respondents was: 42 ± 9 years, mean years of practice was: 14 ± 8 years, males: 46(38%) and females 72(62%) and 95(80%) were family physicians. 56(48%) researched their question prior to calling Motherisk, 106(91%) and passed on the information received to their patient verbatim. The top four resources for information were: 1) The CPS (PDR), 2) textbooks, 3) journals and 4) colleagues. Only 8% used the Medline for gathering information. CONCLUSIONS: Physicians feel that a teratogen information service is an important component in the management of women exposed to drugs, chemicals, radiation and infections diseases etc. during pregnancy. Despite the advent of the electronic age, a minority of the physicians in our survey elected to use electronic means to seek information

Endoplasmic Reticulum Stress signalling - from basic mechanisms to clinical applications

The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes