Abstract
A pivotal hallmark of some cancer cells is the evasion of apoptotic cell death. Importantly, the initiation of apoptosis often results in the activation of caspases, which, in turn, culminates in the generation of proteolytically-activated protein fragments with potentially new or altered roles. Recent investigations have revealed that the activity of a significant number of the protease-generated, activated, pro-apoptotic protein fragments can be curbed via their selective degradation by the N-end rule degradation pathways. Of note, previous work revealed that several proteolytically-generated, pro-apoptotic fragments are unstable in cells, as their destabilizing N-termini target them for proteasomal degradation via the N-end rule degradation pathways. Remarkably, previous studies also showed that the proteolytically-generated anti-apoptotic Lyn kinase protein fragment is targeted for degradation by the UBR1/UBR2 E3 ubiquitin ligases of the N-end rule pathway in chronic myeloid leukemia cells. Crucially, the degradation of cleaved fragment of Lyn by the N-end rule counters imatinib resistance in these cells, implicating a possible linkage between the N-end rule degradation pathway and imatinib resistance. Herein, we highlight recent studies on the role of the N-end rule proteolytic pathways in regulating apoptosis in mammalian cells, and also discuss some possible future directions with respect to apoptotic proteolysis signaling.
Highlights
An Overview of Programmed Apoptotic Cell DeathIn multicellular organisms, cellular homeostasis is maintained through a fine-tuned balance between cell proliferation and cell death [1]
If restricted proteolysis can generate pro-and anti-apoptotic fragments during apoptosis, how do cells regulate and control the output of such proteolytic cascades which regulates the apoptotic execution reactions and impacts cellular fate? A possible avenue for regulating the output of such proteolytic cascades is the difference in metabolic stability among different proteolytically-activated protein fragments generated in each case
Other studies that examined the the effects of CrmA, an inhibitor of interleukin-1b converting enzyme (ICE) encoded by the cowpox virus, on apoptotic cell death further support the role of protease ICE in the induction and regulation of apoptosis
Summary
Cellular homeostasis is maintained through a fine-tuned balance between cell proliferation and cell death [1]. If restricted proteolysis can generate pro-and anti-apoptotic fragments during apoptosis, how do cells regulate and control the output of such proteolytic (caspase/calpain) cascades which regulates the apoptotic execution reactions and impacts cellular fate? Apoptosis is characterized by distinct biochemical features, including membrane blebbing, cellular shrinkage, chromatin condensation (pyknosis), and DNA fragmentation [26] It can be further defined as a mode of cell death that is accompanied by caspases (proteases) activation [27]. The ability of granzyme B to induce apoptotic cell death in the presence of a partially- or completely-inactivated caspase reflects the robustness of this important cellular host defense system
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