Regulating Apoptosis by Degradation: The N-End Rule-Mediated Regulation of Apoptotic Proteolytic Fragments in Mammalian Cells.

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.