Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Recently, we isolated a candidate gene, encoding neuronal apoptosis inhibitor protein (NAIP), for SMA. This gene is homologous to two baculovirus inhibitor of apoptosis proteins (Cp-IAP and Op-IAP) and is partly deleted in individuals with type I SMA. A second SMA candidate gene encoding survival motor neuron (SMN), which is contiguous with the NAIP locus on 5q13.1, was also reported. Here we demonstrate a NAIP-mediated inhibition of apoptosis induced by a variety of signals, and have identified three additional human complementary DNAs and a Drosophila melanogaster sequence that are also homologous to the baculovirus IAPs. The four open reading frames (ORFs) possess three baculoviral inhibition of apoptosis protein repeat (BIR) domains and a carboxy-terminal RING zinc-finger. The human iap genes have a distinct but overlapping pattern of expression in fetal and adult tissues. These proteins significantly increase the number of known apoptotic suppressors.

The inhibitor of apoptosis protein family has been characterized over the past 5 years, initially in baculovirus and more recently in metazoans. The IAPs are a widely expressed gene family of apoptotic inhibitors from both phylogenic and physiologic points of view. The diversity of triggers against which the IAPs suppress apoptosis is greater than that observed for any other family of apoptotic inhibitors including the bcl-2 family. The central mechanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of and by the transcription factor NF-kB. Although evidence for a direct oncogenic role for the IAPs has yet to be delineated, a number of lines of evidence point towards this class of protein playing a role in oncogenesis. The strongest evidence for IAP involvement in cancer is seen in the IAP called survivin. Although not observed in adult dierentiated tissue, survivin is present in most transformed cell lines and cancers tested to date. Survivin has been shown to inhibit caspase directly and apoptosis in general, moreover survivin protein levels correlate inversely with 5 year survival rates in colorectal cancer. Recent data has also implicated survivin in cell cycle control. The second line of evidence for IAP involvement in cancer comes from their emerging role as mediators and regulators of the anti-apoptotic activity of v-Rel and NF-kB transcription factor families. The IAPs have been shown to be induced by NF-kB or v-Rel in multiple cell lines and conversely, HIAP1 and HIAP2 have been shown to activate NF-kB possibly forming a positive feed-back loop. Overall a picture consistent with an IAP role in tumour progression rather than tumour initiation is emerging making the IAPs an attractive therapeutic target.Keywords: inhibitor of apoptosis; IAP; programmed cell death; BIR; RING ®nger; CARD; NAIP; survivin; NF-kB; caspase Part A. The IAP familyThe ®rst Inhibitor of Apoptosis (IAP) proteins were identi®ed in 1993 and 1994 in the baculoviruses Cydia pomonella granulosis virus (CpGV) and Orgyia pseudotsugata nuclear polyhedrosis virus (OpMNPV) by the laboratory of Lois Miller (Crook et al., 1993;Birnbaum et al., 1994). The Miller lab utilized an assay in which infection by a mutant strain of a third baculovirus, Autographa californica nuclear polyhedrosis virus (AcMNPV) results in an unconstrained host lepidopteran SF-21 cell apoptosis. (The natural host cell apoptotic response to viral infection is usually eectively suppressed by the infecting baculovirus). Employing this assay, the CpGV and OpMNPV genomes were screened for loci which would suppress this cell death, resulting in the identi®cation of founding members of a new class of anti-apoptotic genes encoding Cp-IAP and Op-IAP, two proteins which share both homology and the ability to block apoptosis by a wide number of apoptotic triggers (Tables 1, 2 and 5). BIR and RING Zn ®nger domainsThere exists in the baculoviral IAPs two de®ning motifs. The ®rst of these is the B...

Iimmune regulatory proteins such as CIITA, NAIP, IPAF, NOD1, NOD2, NALP1, cryopyrin/ NALP3 are members of a family characterized by the presence of a nucleotide-binding domain (NBD) and leucine-rich repeats (LRR). Members of this gene family encode a protein structure similar to the NB-LRR subgroup of disease-resistance genes in plants and are involved in the sensing of pathogenic products and the regulation of cell signaling and apoptosis. Several members of this family have been associated with immunologic disorders. NOD2 for instance is associated with both Crohn's disease and Blau syndrome.