Effectors of Cell Death

Additionally, Bax can form heterodimers with Bcl-2 or Bcl-XL. This leads to the subsequent inability of Bcl-2 or Bcl-XL to homodimerize, resulting in a suppression of their protective effects against cell death. Recently, further characterization of the Bcl-2 family has revealed that unbound (unphosphorylated) cytoplasmic Bad also selectively heterodimerizes with Bcl-2 or Bcl-XL, displacing Bax and promoting cell death by creating a cytoplasmic pool of free Bax (25-29). 

On the other hand, Bcl-2 serves as a checkpoint for Bax activation by conferring a protective effect through its heterodimerization with Bax, thus preventing formation of ion channels in the mitochondrial membrane. Indeed, overexpression of Bcl-2 results in abnormally high numbers of neurons surviving beyond the perinatal period, while Bcl-2-targeted deletion results in increased neuronal cell death (described later). 

Several lines of evidence suggest that an additional, finer level of control over Bcl-2-Bax interaction may be achieved by the participation of related family members such as Bad. In the retina, Bad is expressed predominantly by ganglion cells (42). Normally, Bad is sequestered in the cytoplasm by the 14-3-3 class of proteins. Extracellular growth or survival factors appear to affect survival, in part, through 

Interestingly, the pro-apoptotic effects of Bad are blocked by the immunosuppressants cyclosporin (CsA) and FK506. In a model of transient ischemia/reperfusion following middle cerebral artery occlusion, both compounds reduced cerebral infarct volume to 30% of control (49). Blockade of calcineurin-mediated dephosphorylation of Bad is a potential mechanism for this effect. Thus phosphorylated, Bad remains sequestered in the cytoplasm and is unable to bind to Bcl-2 (or Bcl-XL), thereby allowing Bcl-2 to exert its protective effect. Regulating expression of specific members of the Bcl-2 family by targeted gene expression is another potential therapeutic tool. This approach is covered in Chapter 11. 

---

Lorenzo HK, Susin SA, Penninger J, Kroemer G. 1999. Apoptosis inducing factor (AIF) a phylogenetically old, cas-pase-independent effector of cell death. Cell Death Differ. 6 516-24... 

Kumar S, Lavin MF (1996) The ICE family of cysteine proteases as effectors of cell death. Cell Death Differ 3 255-267... 

---