A matter of life or death: targeting MCL-1 in multiple myeloma
[thesis]
Anne Slomp
Regulation of apoptosis by BCL-2 proteins Activation of caspases through the intrinsic apoptosis pathway is dependent on mitochondrial outer membrane permeabilization (MOMP) by BAX and BAK ( Figure 2 ). This results in leakage of cytochrome C, which activates caspase activator APAF1. 20 To explain the mechanism of BAX and BAK activation, three models of interactions between BCL-2 proteins have been described. 21 According to the direct activation model, some BH3-only proteins ('activators')
more »
... ctly bind and activate effectors BAX and BAK. Other BH3-only proteins ('sensitizers') are unable to do this, but in turn function by binding to pro-survival proteins, which then release bound activators. In the indirect activation model, BH3-only proteins solely function as neutralizers of pro-survival proteins, which then release BAX and BAK. As a result, BAX and BAK are activated spontaneously or by an unknown modification, which leads to apoptosis. These two models are not mutually exclusive, and currently a third and unified model is considered most likely. In this unified model, pro-survival proteins sequester both BH3-only proteins and BAX and BAK. When upregulated, BH3-only proteins act by neutralizing prosurvival proteins as well as by activating BAX and BAK, leading to MOMP and subsequent caspase activation. 21,22 The common factor among all BCL-2 family proteins is the presence of BH domains (Figure 3 ). BH3-only proteins are named thus because they only contain a BH3-domain. Pro-survival BCL-2 proteins, as well as BAX and BAK, contain four BH domains and therefore have a similar overall structure. 21,23 Most BCL-2 proteins contain a transmembrane domain that allows them to localize to intracellular membranes. In some cases, BCL-2 proteins can receive protein modifications that lead to differences in activity, binding affinity, or degradation. 24 MCL-1 is exemplary in this regard, as it is the only BCL-2 family member whose N-terminal tail is rich in putative and experimentally confirmed modification sites, which are targets for phosphorylation, ubiquitination, and cleavage. 25
doi:10.33540/323
fatcat:ehli3f7ilfgnte2si5f7jmjmum