Identification of a novel antiapoptotic protein that antagonizes ASK1 and CAD activities.
Diverse stimuli initiate the activation of apoptotic signaling pathways that often causes nuclear DNA fragmentation. Here, we report a new antiapoptotic protein, a caspase-activated DNase (CAD) inhibitor that interacts with ASK1 (CIIA). CIIA, by binding to apoptosis signal-regulating kinase 1 (ASK1), inhibits oligomerization-induced ASK1 activation. CIIA also associates with CAD and inhibits the nuclease activity of CAD without affecting caspase-3-mediated ICAD cleavage. Overexpressed CIIA reduces H2O2- and tumor necrosis factor-alpha-induced apoptosis. CIIA antisense oligonucleotides, which abolish expression of endogenous CIIA in murine L929 cells, block the inhibitory effect of CIIA on ASK1 activation, deoxyribonucleic acid fragmentation, and apoptosis. These findings suggest that CIIA is an endogenous antagonist of both ASK1- and CAD-mediated signaling.
Cho
Ssang-Goo
SG
Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea.
Kim
Jin Woo
JW
Lee
Yong Hee
YH
Hwang
Hyun Sub
HS
Kim
Mi-Sung
MS
Ryoo
Kanghyun
K
Kim
Myung Jin
MJ
Noh
Kyung Tae
KT
Kim
Eun Kyung
EK
Cho
Jun-Ho
JH
Yoon
Kyoung Wan
KW
Cho
Eun-Gyung
EG
Park
Hee-Sae
HS
Chi
Sung Wook
SW
Lee
Min-Jae
MJ
Kang
Sang Sun
SS
Ichijo
Hidenori
H
Choi
Eui-Ju
EJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053938:DNA Fragmentation / Q000502:physiology; D003851:Deoxyribonucleases / Q000037:antagonists & inhibitors*; D006861:Hydrogen Peroxide / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482859:Map3k5 protein, mouse; D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease