Departments of 1Pathology, 2Graduate Program in

Inhibitors of apoptosis (IAPs) are a diverse group of signaling molecules that function in a wide range of cellular roles, from the inhibition of caspases to the promotion of cell-cycle progression. These diverse functions may well be linked to the many different domains that are contained within different proteins in the family. IAP family members were first described as inhibitors of apoptosis in baculoviruses, and are therefore identified by the presence of baculovirus IAP repeat (BIR) domains. However, it is becoming increasingly evident that, although the family-defining BIR domain is highly conserved, distinct BIR domains, even within the same protein, have different functions (Eckelman et al., 2006; Srinivasula and Ashwell, 2008). Additionally, RING domains, which have been described in many proteins to have E3 ubiquitin ligase function, are present in several IAP family members. Two IAPs, c-IAP1 (also known as BIRC2) and c-IAP2 (also known as BIRC3), each contain a caspase-recruitment domain (CARD), which is thought to mediate protein-protein interactions. Furthermore, some unique protein domains are found within the IAP family, including a nucleotide-binding and oligomerization domain (NOD) and a leucine-rich repeat (LRR) in neuronal apoptosis inhibitory protein (NAIP; also known as BIRC1) (Fritz et al., 2006), and a ubiquitin-conjugating (UBC) domain in Apollon (also known as BIRC6) (Bartke et al., 2004). X-linked IAP (XIAP; also known as BIRC4) is the best-characterized member of the IAP family and a potent inhibitor of caspases. Because it is overexpressed in numerous malignancies, it has been pursued as a potential therapeutic target for the treatment of cancers. In the past few years, several synthetic small-molecule IAP antagonists have been produced and, in addition to demonstrating their therapeutic potential, studies performed using these drugs have been very informative to the field of IAP biology. Beyond their inhibitory effects on XIAP, these compounds also act on other members of the family, such as c-IAP1 an