Irreversible perturbations in the homeostasis of the endoplasmic reticulum (ER) are thought to lead to apoptosis and cell loss in a number of important human diseases, including Alzheimer disease, Parkinson disease, and type 2 diabetes. However, the exact mechanisms that lead from ER stress to cell death remain incompletely understood. Recent work has shown that the BCL-2 family of proteins plays a central role in regulating this form of cell death, both locally at the ER and from a distance at the mitochondrial membrane.
"These effects of BCL-2 proteins appear to involve activation of IP3R channel gating by an allosteric mechanism that sensitizes the channel to low inositol 1,4,5-tris- phosphate concentrations and accounts for the reduced steady-state ER Ca 2þ levels ( White et al. 2005 ; Eckenrode et al. 2010). At least for BCL-2 , ER calcium regulation appears to be modulated by phosphorylation as phosphorylated BCL-2 , which resides primarily at the ER , cannot reduce basal ER Ca 2þ levels ( Bassik et al. 2004 ; Oakes et al. 2006 ) . Other studies have found instead that inter - action between IP3R and BCL-2 results in in hibition of IP3R and consequently a reduction in stress - induced IP3R - mediated Ca 2þ release , elevation of cytosolic calcium and mitochon - drial calcium overload . "
[Show abstract][Hide abstract] ABSTRACT: BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
Cold Spring Harbor perspectives in biology 02/2013; 5(2). DOI:10.1101/cshperspect.a008722 · 8.68 Impact Factor
"In addition, edelfosine-induced apoptosis in pancreatic cancer cells involves caspase-8 activation and persistent activation of JNK. Members of the Bcl-2 family are also involved in the regulation of cell death induced by ER stress (Oakes et al., 2006). In normal conditions, mammalian cells express low levels of Bax, which is predominantly a soluble monomeric protein in the cytosol (Hsu et al., 1997). "
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspase- and mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH(2)-terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 α-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.
"in cells. Phosphorylation of BCL-2 by JNK in a non-structured loop occurs at the ER membrane, negatively regulating its anti-apoptotic activity , in addition to its ability to control the ER calcium content  . Purification of the native protein complexes containing BCL- 2 at the ER membrane identified the phosphatase PP2A  as an interacting partner that dephosphorylates the sites targeted by JNK. "
[Show abstract][Hide abstract] ABSTRACT: The assembling of distinct signaling protein complexes at the endoplasmic reticulum (ER) membrane controls several stress responses related to calcium homeostasis, autophagy, ER morphogenesis and protein folding. Diverse pathological conditions interfere with the function of the ER altering protein folding, a condition known as "ER stress". Adaptation to ER stress depends on the activation of the unfolded protein response (UPR) and protein degradation pathways such as autophagy. Under chronic or irreversible ER stress, cells undergo apoptosis, where the BCL-2 protein family plays a crucial role at the mitochondria to trigger cytochrome c release and apoptosome assembly. Several BCL2 family members also regulate physiological processes at the ER through dynamic interactomes. Here we provide a comprehensive view of the roles of the BCL-2 family of proteins in mediating the molecular crosstalk between the ER and mitochondria to initiate apoptosis, in addition to their emerging functions in adaptation to stress, including autophagy, UPR, calcium homeostasis and organelle morphogenesis. We envision a model where BCL-2-containing complexes may operate as stress rheostats that, beyond their known apoptosis functions at the mitochondria, determine the amplitude and kinetics of adaptive responses against ER-related injuries. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.
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