Bcl-2 family members play a pivotal role in the intrinsic (mitochondrial) pathway of apoptosis. The “founding” protein, Bcl-2, was first discovered in human B cell follicular lymphoma cells carrying the t(14; 18) chromosomal translocation. Most lymphomas of this type have the breakpoint located in the Bcl-2 gene. Over-ex
The anti-apoptotic members include proteins such as Bcl-2, Bc1-XL, and Mcl-1. Bcl-2 protects against diverse cytotoxic insults that can trigger apoptosis such as starvation of growth factors, loss of cell attachment to extracellular matrix, Fas-stimulation and cytotoxic T-cell killing. Over-ex
BH3-only members can engage pro-survival proteins by the interaction of BH3 domains. The pro-apoptotic activity of BH3-only members is kept in check by either transcriptional control or post-translational modification. They serve as sensors for initiating the intrinsic apoptotic pathway in response to selective stimuli. For example, Bid is engaged through the activation of death receptors, while Noxa and Puma respond to DNA damage. Bim and Bad can be activated by multiple stimuli including growth factor deprivation, detachment from the cell matrix, chemotherapeutic agents or UV treatments. Studies using knockout mice of BH3-only proteins in certain types of cells confer resistance to selective apoptotic stimuli. For example, loss of Bim renders lymphocytes resistant to paclitaxel, ionomycin and cytokine deprivation induced apoptosis while loss of Bad in mammary epithelial cells confers some resistance to withdrawal of epidermal growth factor. Moreover, Noxa-deficient cells are partially resistant to DNA-damaged induced apoptosis. Overall, the redundancy of BH3-only proteins creates a robust control system that integrates responses to different stimuli.
After BH3-only proteins sense death stimuli, they need to activate Bax and Bak to initiate commitment to apoptosis. The first pro-apoptotic homolog, Bax, was first described as a protein that counteracted the pro-survival function of Bcl-2. Overex
Bax and Bak in concert are an essential gateway for activation of caspases in the intrinsic apoptotic pathway, but there are debates as to how BH3-only proteins lead to the activation of Bax and Bak. The direct binding model suggests that the “activators” of BH3-only proteins such as Bid and Bim can directly activate Bax and Bak. Bad or Bik act as “sensitizers,” that sequester the pro-survival proteins and allow unbound Bax and Bak to oligomerize. Inconsistent observations for binding of endogenous Bid and Bim to Bax or Bak lead to the suggestion that they operate at a “hit-and-run” fashion. The displacement model suggests that BH3-only proteins can displace the binding of Bax or Bak to pro-survival proteins that sequester their active forms. Chen et al recently demonstrated the differential affinity of BH3-only proteins for pro-survival proteins. Using peptides mapped to BH3 sequence of BH3-only proteins, it was shown that certain molecules such as Puma and Bim can bind to all pro survival proteins. Bad can counteract Bcl-2 and Bcl-XL but not Mcl-1 while Noxa complements only by interacting with Mcl-1. By engineering Noxa to enhance promiscuous binding to all pro-survival proteins, effective killing occurred. This was further supported by the observation of Willies et al showing that both Noxa and Bad are required to neutralize Mcl-1 and Bcl-XL respectively to drive efficient apoptosis mediated by Bak. A recent report showed 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 while others showed mitochondrial permeabilization relies on BH3-only proteins engaging pro-survival Bcl-2 relatives and not Bak. These results further support the notion that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak.