Abstract
Apoptosis is a cell suicide process that is essential for development, tissue homeostasis and human health. Impaired apoptosis is associated with a variety of human diseases, including neurodegenerative disorders, autoimmunity and cancer. As the levels of pro- and anti-apoptotic proteins can determine the life or death of cells, tight regulation of these proteins is critical. The ubiquitin proteasome system (UPS) is essential for maintaining protein turnover, which can either trigger or inhibit apoptosis. In this review, we will describe the E3 ligases that regulate the levels of pro- and anti-apoptotic proteins and assisting proteins that regulate the levels of these E3 ligases. We will provide examples of apoptotic cell death modulations using the UPS, determined by positive and negative feedback loop reactions. Specifically, we will review how the stability of p53, Bcl-2 family members and IAPs (Inhibitor of Apoptosis proteins) are regulated upon initiation of apoptosis. As increased levels of oncogenes and decreased levels of tumor suppressor proteins can promote tumorigenesis, targeting these pathways offers opportunities to develop novel anti-cancer therapies, which act by recruiting the UPS for the effective and selective killing of cancer cells.
Highlights
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
CIAP1 and cIAP2 can bind to but not inhibit caspases [24,25]. Both XIAP and cIAPs contain a RING (Really Interesting New Gene) domain, which enables these proteins to function as E3 ligases [26,27,28,29]
The induction of BID, BAK and BAX promotes the permeabilization of the outer mitochondrial membrane and amplifies the caspase activation process [191,192]. p53 increases the transcription of the pro-apoptotic XIAP-antagonist, ARTS, which relieves caspases from inhibition by XIAP, leading to the cleavage of BID and mitochondrial outer membrane permeabilization (MOMP) [190,193]
Summary
The Ubiquitin Proteasome System (UPS) is responsible for the regulated degradation of intracellular proteins [43,44,45]. Ubiquitylation is the post-translational conjugation of the 76 amino acid ubiquitin protein, which tags proteins destined for degradation via the 26S proteasome [45,46,47,48,49,50]. The K48 chains are involved in proteasome-dependent degradation [68]. The E1 enzyme forms an ATP-dependent thioester linkage with the carboxyl-terminus of ubiquitin; E1 is not substrate-specific [79]. The E3 ligases are substrate-specific and are essential for the final transfer of the activated ubiquitin from the E2 enzyme to the lysine residue onto the target protein [80,81,82]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
