[Abstract unavailable

The efficient functioning of the endoplasmic reticulum (ER) is essential for most cellular activities and survival. Conditions that interfere with ER function lead to the accumulation and aggregation of unfolded proteins. ER transmembrane receptors detect the onset of ER stress and initiate the unfolded protein response (UPR) to restore normal ER function. If the stress is prolonged, or the adaptive response fails, apoptotic cell death ensues. Many studies have focused on how this failure initiates apoptosis, as ER stress-induced apoptosis is implicated in the pathophysiology of several neurodegenerative and cardiovascular diseases. In this review, we examine the role of the molecules that are activated during the UPR in order to identify the molecular switch from the adaptive phase to apoptosis. We discuss how the activation of these molecules leads to the commitment of death and the mechanisms that are responsible for the final demise of the cell.

The labyrinth of the endoplasmic reticulum (ER) interweaves the cytosol and connects to the nucleus, mitochondria, and the plasma membrane. In the lumen of the ER, the essential function of lipid synthesis, Ca(2+) storage, folding, and maturation of proteins take place. Therefore, the tight regulation and maintenance of ER homeostasis is vital. Disturbance of the Ca(2+) homeostasis during hypoxia, or imbalance between the demand and capacity of the protein-folding apparatus, initiates an adaptive response of the cell, termed the unfolded protein response (UPR, ER stress response). As a result, ER-localized chaperones are induced, protein synthesis is slowed down, and a protein degrading system is initiated. However, if the ER stress cannot be alleviated, it culminates in apoptosis. This paper reviews the newly outlined signaling pathways of the unfolded protein response and describes the central role of caspase-12 in the initiation of cell death. The complex role of the ER and its signaling pathways provides a novel angle on apoptosis research and may offer a key to apoptosis-associated diseases.

No abstract

Tissue transglutaminase (TGase2) is a protein-crosslinking enzyme known to be associated with the in vivo apoptosis program. Here we report that apoptosis could be induced in TGase2 ؊/؊ mice; however, the clearance of apoptotic cells was defective during the involution of thymus elicited by dexamethasone, anti-CD3 antibody, or ␥-irradiation, and in the liver after induced hyperplasia. The lack of TGase2 prevented the production of active transforming growth factor-␤1 in macrophages exposed to apoptotic cells, which is required for the up-regulation of TGase2 in the thymus in vivo, for accelerating deletion of CD4؉CD8؉ cells and for efficient phagocytosis of apoptotic bodies. The deficiency is associated with the development of splenomegaly, autoantibodies, and immune complex glomerulonephritis in TGase2 ؊/؊ mice. These findings have broad implications not only for diseases linked to inflammation and autoimmunity but also for understanding the interrelationship between the apoptosis and phagocytosis process.

The endoplasmic reticulum (ER) is the main site for protein folding, lipid biosynthesis, and calcium storage in the cell. Disturbances of these critical cellular functions lead to ER stress. The ER responds to disturbances in its homeostasis by launching an adaptive signal transduction pathway, known as the unfolded protein response (UPR). The UPR strives to maintain ER function during stress; however, if the stress is not resolved, apoptotic responses are activated that involve cross talk between the ER and mitochondria. In addition, ER stress is also known to induce autophagy to counteract XBP-1-mediated ER expansion and assist in the degradation of unfolded proteins. One family of proteins involved in the regulation of apoptosis is that of B-cell lymphoma protein 2 (Bcl-2). Complex interactions among the three subgroups within the Bcl-2 family [the antiapoptotic, the multidomain proapoptotic, and the Bcl-2 homology domain 3 (BH3)-only members] control the signaling events of apoptosis upstream of mitochondrial outer membrane permeabilization. These proteins were found to have diverse subcellular locations to aid in the response to varied intrinsic and extrinsic stimuli. Of recent interest is the presence of the Bcl-2 family at the ER. Here, we review the involvement of proteins from each of the three Bcl-2 family subgroups in the maintenance of ER homeostasis and their participation in ER stress signal transduction pathways.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug that selectively induces apoptosis in a variety of cancer cells by interacting with death receptors DR4 and DR5. TRAIL can also bind to decoy receptors (DcR1, DcR2, and osteoprotegerin receptor) that cannot induce apoptosis. The occurrence of DR5-responsive tumor cells indicates that a DR5 receptor-specific TRAIL variant will permit tumor-selective therapies. By using the automatic design algorithm FOLD-X, we successfully generated DR5-selective TRAIL variants. These variants do not induce apoptosis in DR4-responsive cell lines but show a large increase in biological activity in DR5-responsive cancer cell lines. Even wild-type TRAIL-insensitive ovarian cancer cell lines could be brought into apoptosis. In addition, our results demonstrate that there is no requirement for antibody-mediated cross-linking or membrane-bound TRAIL to induce apoptosis through DR5.computational protein design ͉ receptor selectivity ͉ biopharmaceutical ͉ death receptor ͉ apoptosis-inducing ligand 2 T umor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is currently attracting great interest as a potential anticancer therapeutic. TRAIL, in its soluble form, selectively induces apoptosis in tumor cells in vitro and in vivo by a death receptor-mediated process. Unlike other apoptosis-inducing TNF family members, soluble TRAIL appears to be inactive against normal healthy tissue (1). Reports in which TRAIL induces apoptosis in normal cells could be attributed to the specific preparations of TRAIL used (2). TRAIL shows a high degree of promiscuity as it binds to five cognate receptors: DR4 (TRAIL-R1) and DR5 (TRAIL-R2) and the decoy receptors DcR1 (TRAIL-R3), DcR2 (TRAIL-R4), and osteoprotegerin (OPG) (3). Upon binding to TRAIL, DR4 and DR5 receptors recruit Fas-associated death domain, which binds and activates the initiator caspase 8, leading to apoptosis (4-6). DcR1 or DcR2 do not contain a death domain or a truncated death domain, respectively, and therefore could prevent apoptosis by sequestering available TRAIL or by interfering in the formation of a TRAIL-DR4 or -DR5 signaling complex (7).Use of TRAIL receptor-selective variants could permit better tumor-specific therapies through escape from the decoy receptor-mediated antagonism, resulting in a lower administrated dose with possibly fewer side effects and as alternatives to existing agonistic receptor antibodies (8-10). In experimental anticancer treatments, the receptors DR4 and͞or DR5 were shown to be up-regulated after treatment with DNA-damaging chemotherapeutic drugs, and the response to TRAIL-induced apoptosis was significantly increased (3, 11). In addition, irradiation appears to specifically up-regulate DR5 receptor expression, and the combination of irradiation and TRAIL treatment has been demonstrated to have an additive or synergistic effect (12). Thus, we chose to develop DR5 receptor-selective TRAIL variants by using a computational design strategy. Computatio...

The mitochondrial pathway to apoptosis is a major pathway of physiological cell death in vertebrates. The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP). BCL-2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro-apoptotic B cell lymphoma (BCL)-2 proteins, BCL-2 associated x protein and BCL-2 antagonist killer 1 induce MOMP whereas the anti-apoptotic BCL-2 proteins, BCL-2, BCL-xl and myeloid cell leukaemia 1 prevent MOMP from occurring. The release of pro-apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades. These pathways are important for normal cellular homeostasis and play key roles in the pathogenesis of many diseases. In this review, we will provide a brief overview of the mitochondrial death pathway and focus on a selection of diseases whose pathogenesis involves the mitochondrial death pathway and we will examine the various pharmacological approaches that target this pathway.