Apoptosis, or programmed cell death, is a genetically regulated process with critical roles in development and homeostasis in metazoans (1). Deficient apoptosis leads to the absence of normal cell death and contributes to the development and progression of human cancers (2). Apoptotic cell death can be initiated through the engagement of cell surface proapoptotic receptors by their specific ligands or by changes in internal cellular integrity (3, 4). Both of these pathways converge at the activation of caspases, cysteine-dependent aspartyl-specific proteases that comprise the effector arm of apoptotic cell death (5, 6). The intrinsic or mitochondrial pathway is initiated by developmental cues or cellular stress signals. These signals activate Bcl-2 homology 3 (BH3) 3 proteins, leading to neutralization of the antiapoptotic proteins, such as Bcl-2, Bcl-x L , or Mcl-1, activation of proapoptotic proteins Bax and Bak, and subsequent disruption of mitochondrial membrane potential (7). The resulting release of cytochrome c from the mitochondria into the cytoplasm leads to Apaf-1-mediated caspase-9 activation and consequent activation of effector caspases-3 and -7 and culminates in cell death.The extrinsic apoptotic pathway is triggered when proapoptotic receptors such as Fas or death receptor 5 (DR5) are engaged by their respective ligands, resulting in recruitment of the adaptor protein FADD and the apical caspases 8-or -10 (3). Incorporation of these caspases into the receptorassociated death-inducing signaling complex causes their autoactivation and leads to ensuing activation of effector caspases-3 and -7. In most cell types (type II cells), amplification of extrinsic pathway signaling through caspase-8-mediated activation of the BH3-only protein Bid is critical for efficient execution of apoptosis (8, 9); in type I cells direct activation of effector caspases by caspase-8 is sufficient. Bid plays an important role in a number of cellular pathways including regulation of Fas-and TNFR1-mediated hepatocellular injury (9 -13). In addition to stimulation by their respective ligands, proapoptotic receptors can be engaged by agonistic antibodies (14). DR5 agonist antibody (PRO95780) binds DR5 tightly and selectively, triggering apoptosis in various types of cancer cells and inhibiting tumor xenograft growth in vivo (15,16).IAP proteins represent the ultimate line of defense against cellular suicide by regulating caspase activity and preventing caspase activation (17). c-IAP1 and c-IAP2 are components of TNF receptor (TNFR) complexes where they modulate apoptotic signaling and caspase-8 activation (18 -20). X chromosome-linked IAP (XIAP) is the only true endogenous inhibitor of caspases because other IAP proteins exhibit weak binding to and inhibition of caspases (21). XIAP inhibits caspases-3 and -7 using the linker region between its baculoviral IAP-repeat (BIR) domain 1 (BIR1) and BIR2 as well as the BIR2 domain, whereas inhibition of caspase-9 relies on the binding of the BIR3 domain to an N-terminal