Part 1

1.1 Direct vs. Indirect activation model?

The direct activation model requires activation of the BAX and BAK molecules from a direct activator (tBID, BIM, and/or PUMA). In this model the sensitizers/derepressors serve only as an additional level of regulation over the anti-apoptotic repertoire. Liposome studies have shown that tBID, BIM, PUMA, and their BH3 mimetics can directly activate BAX and BAK, resulting in MOMP (Gavathiotis et al., 2008; Lovell et al., 2008).

The indirect activation/neutralisation/depressor model competes with the direct activation model. This model assumes a small sub population of constitutively active BAX and BAK are sequestered by anti-apoptotic BCL-2 members and that for MOMP to occur, the BH3-only proteins function exclusively to free the sequestered activated BAX and BAK molecules. This model discounts any direct activators. Active isoforms of BAX (BAXβ) have been shown to exist in the cytosol (Fu et al., 2008). BAXβ spontaneously translocates to the OMM and undergoes oligomerisation. BAXβ can also associate and promote BAXα activation. BAX and BAK may not require direct activators for activation, but MOMP has been shown to occur most efficiently when direct activators and sensitizers/derpressors work in unison (Merino et al., 2009).

The two aforementioned models both have contrasting data for and against them. The embedded together model (Leber et al., 2007) combines features from both the direct and indirect activation models in an attempt to reconcile both models. In this model the BCL-2 family proteins undergo structural rearrangement after interaction with the OMM. The different models highlight the complex nature of the BCL-2 family and that we have yet to fully understand these proteins and their interactions.

Figure 1: An overview of the intrinsic and extrinsic apoptotic pathways
(Elkholi et al., 2011).

1.2 Understanding the BCL-2 family in relation to cancer

The BCL-2 family are involved with many cancer types. To understand the role of the BCL-2 family in cancer, it is important to first understand the normal cellular roles these proteins play in regards to the intrinsic death pathway. How do the BCL-2 proteins function? How are they regulated? The answer to these two questions elucidates their role in cancer and how they can be targeted for treatment.

Part 2
References

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