All along the watchtower: on the regulation of apoptosis regulators

Abstract

Members of the expanding family of Bcl-2-like proteins have emerged as important regulators of programmed cell death, and recent studies have unearthed numerous mechanisms for regulating the function of these death agonists and antagonists. In addition to the transcriptional control of gene expression, these mechanisms include posttranslational events such as phosphorylation, proteolysis, and the induction of conformational changes, which may either activate or inactivate these molecules. Interaction with homologous and nonhomologous proteins and specific subcellular targeting of Bcl-2-like proteins are other means of fine-tuning the cellular response to noxious stimuli. Recently, considerable attention has turned to the regulation of so-called BH3-only molecules, which appear to act as stress sensors that relay signals to other pro- or antiapoptotic family members. We discuss how the regulation of these apoptosis regulators may control the ultimate fate of the cell.

Epstein‐Barr virus‐encoded latent membrane protein 1 promotes stress‐induced apoptosis upstream of caspase‐2‐dependent mitochondrial perturbation

“…7 Bcl-2, an anti-apoptotic protein that resides in the mitochondrial membrane, prevents the release of cytochrome c, whereas pro-apoptotic members of the Bcl-2 family promote this process. 8 Recent studies have implicated caspase-2 as an upstream regulator of the release of mitochondrial constituents, including cytochrome c and smac (second mitochondrial activator of caspases), in cellular stress-induced apoptosis. 9 -12 Cell type-or stimulus-specific differences in the requirement for caspase-2 need to be taken into account since DNA-damaging agents were previously found to trigger apoptosis in lymphoblasts from caspase-2-defective mice.…”

Big wheel keeps on turning: apoptosome regulation and its role in chemoresistance

“…The mechanism underlying this sequestration remains unknown, but could involve post-translational modifications of Apaf-1, thus targeting this protein to lipid raft domains. These studies further underscore the fundamental importance of correct compartmentalization of the cell death machinery, 95 and suggest that targeting of lipid rafts could serve to promote sensitivity of B lymphomas to conventional anticancer treatment.…”

Apoptosis, Oxidative Stress and Neurological Disease

“…The apoptotic process is also essential for the maintenance of cellular homeostasis in adults, especially adult mammals, which during their long lives are exposed to many pathological signals which may induce cell death (2). Deregulation of apoptotic pathways may be a primary event in the onset of various diseases, since very high and very low apoptotic levels can lead to degenerative and proliferative pathologies, respectively (3). It has been shown that pathologies such as autoimmunity and cancer are related to a deficit in apoptotic mechanisms, while an increase in apoptotic levels may determine acute and chronic degenerative diseases, such as those of the nervous system, ischemic diseases, immunodeficiency and autoimmunity (3).…”

“…Deregulation of apoptotic pathways may be a primary event in the onset of various diseases, since very high and very low apoptotic levels can lead to degenerative and proliferative pathologies, respectively (3). It has been shown that pathologies such as autoimmunity and cancer are related to a deficit in apoptotic mechanisms, while an increase in apoptotic levels may determine acute and chronic degenerative diseases, such as those of the nervous system, ischemic diseases, immunodeficiency and autoimmunity (3). Cells undergoing apoptosis may be identified by numerous morphological modifications that can be detected by light and electron microscopy; these modifications are surprisingly similar in different cell types and species and are irrefutable evidence of an ongoing process (1).…”