1. ^*Molecular Genetics Research Laboratory, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada
2. ^†ApoptoGen, Inc., University of Ottawa, Ottawa, Ontario K1H 8L1, Canada
3. ^‡, Department of Biochemistry and ^¶Department of Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
4. ^§Medical and Biological Laboratories Co., Naka-ku, Nagoya 460, Japan
5. The Institute of Medical Science, Tokai University, Kanagawa 259-11, Japan
6. ^£ To whom correspondence should be addressed.

Abstract

DYSREGULATION of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers¹, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenera-tive disorders, such as spinal muscular atrophy (SMA). Recently, we isolated a candidate gene, encoding neuronal apoptosis inhibitor protein (NAIP)², for SMA. This gene is homologous to two baculovirus inhibitor of apoptosis proteins^3,4 (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 5ql3.1, was also reported5. 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 lAPs. 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.