Emerging evidence suggests that the endoplasmic reticulum (ER) also regulates apoptosis by communicating with mitochondria and by initiating cell-death sig nals of its own. The contribution of the ER to apoptosis is highlighted by the fact that Bcl-2 family members have been localized to ER membranes, in addition to mitochondria, and demonstrated to influence ER homeostasis directly. Calcium release from the ER has been implicated as a key signaling event in many apoptotic models, and, depending on the mode of Ca2+ release, it may directly activate death effectors or influence the mitochondria to undergo apoptotic transitions. A grow-
ing number of ER proteins have been shown to regulate apoptosis, some by inter acting with Bcl-2 family members, and others being caspase substrates. Moreover, recent studies on how stress in the ER is coupled to apoptosis have demonstrated that the ER, like mitochondria, can directly initiate pathways to caspase activation and apoptosis.