Regulation of apoptosis: the ubiquitous way

Abstract

Ubiquitin is a ubiquitously expressed 76 amino acid protein that can be covalently attached to target proteins, leading to their ubiquitination. Many ubiquitinated proteins are degraded by the proteasome, a 2000 kDa ATP-dependent proteolytic complex. Numerous studies have demonstrated that the ubiquitination and proteasome system plays an important role in controlling the levels of various cellular proteins and therefore regulates basic cellular processes such as cell cycle progression, signal transduction, and cell transformation. Ubiquitination also directly affects the function and location of target proteins. Recent studies found that ubiquitination-mediated degradation and change in activity regulate many molecules of the cell death machinery, such as p53, caspases, and Bcl-2 family members. Ring finger-containing members of the IAP (inhibitor of apoptosis) family proteins themselves can function as ubiquitin protein ligases to ubiquitinate their target proteins or promote autoubiquitination. It has been demonstrated that degradation of the IAP proteins is required for apoptosis to occur in some systems, indicating apoptosis proceeds by activating death pathways as well as eliminating "roadblocks" through ubiquitination. These new findings also suggest that ubiquitination is one of the major mechanisms that regulate apoptotic cell death and could be a unique target for therapeutic intervention.

Adenoviral expression of XIAP antisense RNA induces apoptosis in glioma cells and suppresses the growth of xenografts in nude mice

“…Despite the presumed role of XIAP in targeting caspases for proteasomal degradation, 9 the loss of XIAP did not result in an accumulation of procaspases, possibly because of autoactivation and autoprocessing. The loss of XIAP was delayed by the broad-spectrum caspase inhibitor, zVADfmk, suggesting that XIAP was not only depleted by antisense expression but also became a substrate for activated caspases, as previously observed during Ad-XIAP antisense gene therapy for malignant glioma U Naumann et al CD95L-induced apoptosis in these cells.…”

“…8 Further, IAP serve as ubiquitin ligases: they initiate ubiquitinylation of IAP-bound caspases and are therefore responsible for their proteasomal degradation. 9 The mitochondrial protein second mitochondrial activator of caspases (SMAC)/DIABLO promotes apoptosis by eliminating the protective effect of IAP through physical interactions, 10 which repress the ubiquitin ligase activity of XIAP and, to a lesser extent, of cIAP1 and cIAP2. 11 A second, alternative mechanism mediating XIAPdependent protection from apoptosis involves transcriptional activity mediated via the stimulation of NF-kB, which depends on the E3 ubiquitin ligase activity of the RING domain of XIAP.…”

Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation

“…Thus, IAP induction may inhibit apoptosis in several cells [21,31,32]. Because of its ubiquitous distribution and inducible properties, the IAP family serves as cytoprotective machinery under bacterial toxin-stimulated pathophysiological situations [21].…”

Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

“…IAP are ubiquitous, intracellular proteins that regulate apoptotic processes. Previous reports have shown that IAP are able to inhibit apoptosis induced by a wide range of stimuli, including TNF-a, anti-Fas antibodies, oxidative stress, pro-apoptotic members of the Bcl-2 family, cytochrome c, anticancer drugs, and serum withdrawal [29][30][31]. Because of its ubiquitous distribution and inducible property, the IAP family is supposed to serve as cytoprotective machinery under pathophysiological situations.…”