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J. Biochem, 2003, Vol. 133, No. 6 719-724
© 2003 Japanese Biochemical Society

BIOCHEMISTRY

Apoptosis-Signal Regulating Kinase-1 Is Involved in the Low Potassium–Induced Activation of p38 Mitogen-Activated Protein Kinase and c-Jun in Cultured Cerebellar Granule Neurons

Satoru Yamagishi1,+, Masashi Yamada1, Hisatsugu Koshimizu1, Satomi Takai1, Hiroshi Hatanaka1, Kohsuke Takeda2, Hidenori Ichijo2, Koji Shimoke3 and Toshihiko Ikeuchi3

1 Division of Protein Biosynthesis, Institute for Protein Research, Osaka University, Suita, Osaka; 2 Cell Signaling, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549; 3 Laboratory of Neurobiology, Faculty of Engineering and High Technology Research Center, Kansai University, 3-3-35 Yamate, Suita, Osaka 564-8680

Previously, we reported that p38, which belongs to the mitogen-activated protein kinase (MAPK) superfamily, has an important role in the induction of apoptosis of cultured cerebellar granule neurons. However, the molecular mechanisms upstream of p38 activation remain unclear. Apoptosis signal-regulating kinase-1 (ASK1), a MAPK kinase kinase (MAPKKK) protein, is known to activate both c-Jun N-terminal kinase (JNK) and p38 via MAPK kinase (MKK) 4/7 and MKK3/6, respectively. Here, we examined whether ASK1 is involved in the activation of p38 in the low potassium (LK)-induced apoptosis of cerebellar granule neurons. We found that ASK1 was activated after a change to LK medium. In addition, the expression of ASK1-KM, a dominant-negative form of ASK1, using an adenovirus system was found to inhibit the activation of p38 and c-Jun and to prevent apoptosis. On the other hand, the expression of ASK1-{Delta}N, a constitutively active form of ASK1, activated p38 and c-Jun, but not JNK, another possible downstream target of ASK1. Furthermore, we examined the relationship between phosphatidylinositol 3-kinase (PI3-K) and ASK1. The addition of LY294002, a specific inhibitor of PI3-K, enhanced the ASK1 activity. These results indicate that ASK1 works downstream of PI3-K to regulate the p38–c-Jun pathway and apoptosis in cultured cerebellar granule neurons.

+ To whom correspondence should be addressed at the present address: Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871. Tel: +81-6-6879-3221, Fax: +81-6-6879-3229, E-mail: yamagishi{at}anat2.med.osaka-u.ac.jp


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