Apoptosis-blocking mechanisms of IAP family proteins

ss3

MS13-3 Yoshihide

Prevention

of Cell Death

by Bcl-2

Tsujimoto

Osaka University Medical School, Department of Medical Genetics

Biomedical

Research

Center

Bcl-2 and its relative Bcl-x,. prevent apoptosis induced by Apoptosis is a tightly regulated suicide mechanism. a variety of stimuli. Several groups including ours have described that Bcl-2 and Bcl-x, prevent cell death by blocking a step(s) leading to the activation of death-driving cystein proteases called caspases. We have shown that Bcl-2 prevents the activation of caspases by blocking mitochondrial dysfunction, particularly membrane potential loss, which seems to be an obligatory step in apoptosis through allowing subsequent release of several mitochondrial apoptogenic factors such as AIF. We studied with isolated mitochondria and suggested that Bcl-2 prevents potential loss by regulating H- flux. we have recently identified two Bcl-2As another part of our efforts to elucidate the Bcl-2 function, interacting proteins, both of which synergize with Bcl-2 in preventing cell death. One IS a novel protein and the other is SMN, a protein implicated in spinal muscular atrophy which is an autosomal recessive disorder and characterized by degeneration of lower motor neurons. Subsequent analyses suggest that disruption of the synergy by Bcl-2 and SMN through mutations in SMN is responsible for disease development. I will present our recent data on these subjects and discuss how the B&2 protein functions.

MSl3_4 MASAYUKI

OLIGODENDROCYTE MIURAI,

SHIN

CELL

DEATH

HISAHARAI&

BY DEATH

RIYA

TAKANOI,

FACTORS SHIN’ICHI

SHOJI?

AND

HIDEYUKI OKAN ‘Dept. of Neuroanatomy, Osaka Univ. Medical School, Suita, Osaka 565-0871, 2Dept. of Neurology, Inst. Medical Sciences, Univ. Tsukuba, Tsukuba, Ibaraki 3050006 Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50 % of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, massive OLG cell deaths have been observed in multiple sclerosis (MS). Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes (OLGs). The addition of TNF-cx to primary cultures of mouse OLGs significantly decreased the number of live OLGs in 72 h. DNA fragmentation was detected in TNF-treated OLGs at 36 h with TUNEL assay. Chemical inhibitors AC-YVAD-CHO (a specific inhibitor of caspase- 1-like proteases) enhanced the survival of OLGs treated with TNF-a, indicating that caspase-l-mediated cell-death pathway are activated in TNF-induced OLG from CASP-II- deficient required to activate caspase-1 both in vivo and in vitro. Oiigodendrocytes resistant to TNF-induced cell death. These results suggest that the activation of caspase- 1 pathway OLG cell death and inhibiton of caspase family may be a novel approach to treat neurodegenerative

MS13-5

cell death. Caspase-I 1 is mice are partially is crucial in TNF-induced diseases such as MS.

APOPTOSIS-BLOCKING MECHANISMS OF IAP FAMILY PROTEINS

RYOSUKE TAKAHASHI Department of Neurology, Tokyo 183-8526

Tokyo

Metropolitan

Institute

for Neuroscience,

Fuchu-shi,

The inhibitor of apoptosis (IAP) family of proteins has an evolutionarily conserved role in regulating programmed cell death in animals ranging from insects to humans. All the IAPs of various species have been shown to block apoptosis when over-expressed in cultured cells and all contain at least one baculovirus IAP repeat (BIR) domain. We have shown that X-linked IAP(XIAP), c-IAP1 and c-IAP2 are direct inhibitors of active 3, 7 and 9, which play critical roles in the execution of apoptosisl)2). Moreover a structure-function revealed that BIR2 is the minimal essential domain of XIAP required

analysis of XIAP for caspase-inhibitory

activity and anti-apoptotic function3). References: 1) Deveraux QL et al. Nature 388, 300, 1997. 2) Roy N et al. EMBO J 76, 69 74, 1997 3) Takahashi R et al. J Biol Chem 273, 7787, 1998