Apoptosis Initiated When BH3 Ligands Engage Multiple Bcl-2 Homologs, Not Bax or Bak

Abstract

A central issue in the regulation of apoptosis by the Bcl-2 family is whether its BH3-only members initiate apoptosis by directly binding to the essential cell-death mediators Bax and Bak, or whether they can act indirectly, by engaging their pro-survival Bcl-2-like relatives. Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak.

BH3-only proteins and their roles in programmed cell death

“…The BH3-only proteins activate apoptosis by binding and neutralizing the prosurvival proteins, allowing Bax/Bak to homo-oligomerize and permeabilize the mitochondria. This displacement model does not require any interaction between the BH3-only proteins and Bax/Bak (Willis et al, 2007). Pro-survival proteins protect cells from apoptosis by sequestering Bax/Bak rather than the 'activator' BH3-only proteins, as suggested by the direct model.…”

“…The BH3 domain seems to be entirely responsible for this interaction, and is absolutely required for the killing activity of the BH3-only proteins. In addition, Bim, Bid and Puma were also found to interact with Bax (Marani et al, 2002;Cartron et al, 2004;Willis et al, 2007). Bim, Bad and Bmf are unstructured in the absence of a binding partner, and only their BH3 domain becomes structured upon binding a pro-survival protein (Hinds et al, 2007).…”

“…Pro-survival proteins protect cells from apoptosis by sequestering Bax/Bak rather than the 'activator' BH3-only proteins, as suggested by the direct model. The differences in the pro-apoptotic potential between BH3-only proteins are explained by the fact that Bim, Puma and Bid are capable of binding to all pro-survival proteins, whereas the others (Bad, Noxa, Hrk, Bik and Bmf) only bind to a subset of these Willis et al, 2007). According to this model, apoptosis occurs when all the pro-survival proteins are effectively neutralized, explaining why Bad (which only binds Bcl-2, Bcl-xL and Bclw) and Noxa (which, in contrast, only binds Mcl-1 and A1) are poor inducers of apoptosis on their own, but efficient inducers as a combination (Willis et al, 2007).…”

The BCL-2 protein family, BH3-mimetics and cancer therapy

“…21 BAX and BAK bind to and are inhibited by different BCL-2-like pro-survival proteins to different extents. 22,23 BOK shares significant homology across all four BH domains to BAX and BAK; however, its role in apoptosis remains unclear, 24 although it may cooperate with BAX in the attrition of primordial follicle oocytes during ageing. 25 The pro-apoptotic BH3-only proteins (BIM, PUMA, BID, BAD, BIK, BMF, NOXA, HRK) share only the BH3 domain with each other and their more distant relatives.…”

The BH3-mimetic ABT-737 targets the apoptotic machinery in cholangiocarcinoma cell lines resulting in synergistic interactions with zoledronic acid

“…For an efficient induction of apoptotic machinery, a complete antagonism of all BCL-2 prosurvival proteins is required [32]. Therefore, ineffective tumor cells killing may be due to a partial neutralization of BCL-2 family members often caused by overexpression of several BCL-2 proteins.…”