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Published 13 October 2003. doi:10.1083/jcb.200303003
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© The Rockefeller University Press, 0021-9525/2003/10/71 $8.00
The Journal of Cell Biology, Volume 163, Number 1, 71-81

Article

 Identification of a novel antiapoptotic protein that antagonizes ASK1 and CAD activities

Ssang-Goo Cho1,2, Jin Woo Kim1, Yong Hee Lee1, Hyun Sub Hwang1, Mi-Sung Kim1, Kanghyun Ryoo1, Myung Jin Kim1, Kyung Tae Noh1, Eun Kyung Kim1, Jun-Ho Cho1, Kyoung Wan Yoon1, Eun-Gyung Cho1, Hee-Sae Park1, Sung Wook Chi1, Min-Jae Lee3, Sang Sun Kang4, Hidenori Ichijo5 and Eui-Ju Choi1

1 National Creative Research Initiative Center for Cell Death, Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea
2 Department of Animal Biotechnology, Konkuk University, Seoul 143-702, Korea
3 Department of Lab Animal Research, Samsung Biomedical Research Institute, Seoul 135-701, Korea
4 Division of Science Education, Chungbuk National University, Chongju 361-763, Korea
5 Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Address correspondence to Eui-Ju Choi, Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea. Tel.: 82-2-3290-3446. Fax: 82-2-3290-4741. email: ejchoi{at}korea.ac.kr

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.

Key Words: apoptosis; apoptosis signal-regulating kinase 1; caspase-activated DNase; stress-activated protein kinase; c-Jun NH2-terminal kinase

S.-G. Cho, J.W. Kim, and Y.H. Lee contributed equally to this work.

The online version of this paper contains supplemental material.

Abbreviations used in this paper: ASK1, apoptosis signal-regulating kinase 1; CAD, caspase-activated DNase; CIIA, CAD inhibitor that interacts with ASK1; DFF, DNA fragmentation factor; His, hexahistidine; JNK, c-Jun NH2-terminal kinase; MEF, mouse embryonic fibroblast; MEKK1, MAPK/extracellular signal–regulated kinase kinase kinase 1; SAPK, stress-activated protein kinase.


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