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Originally published In Press as doi:10.1074/jbc.M003425200 on October 11, 2000

J. Biol. Chem., Vol. 276, Issue 2, 999-1004, January 12, 2001
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Apoptosis Signal-regulating Kinase 1 (ASK1) Is an Intracellular Inducer of Keratinocyte Differentiation*

Koji SayamaDagger §, Yasushi HanakawaDagger , Yuji ShirakataDagger , Kenshi YamasakiDagger , Yasuhiro Sawada, Lin Sun||, Kiyofumi Yamanishi**, Hidenori Ichijo, and Koji HashimotoDagger

From the Dagger  Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295, Japan,  Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan, the || Department of Dermatology, The Second Affiliated Hospital of Dalian Medical University, Dalian, P.R. China, and the ** Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan

Cells differentiate in response to various extracellular stimuli. This cellular response requires intracellular signaling pathways. The mitogen-activated protein (MAP) kinase cascade is a core signal transduction pathway that determines the fate of many kinds of cell. MAP kinase kinase kinase activates MAP kinase kinase, which in turn activates MAP kinase. Apoptosis signal-regulating kinase (ASK1) was identified as a MAP kinase kinase kinase involved in the stress-induced apoptosis-signaling cascade that activates the SEK1-JNK and MKK3/MKK6-p38 MAP kinase cascades. Expression of the constitutively active form of ASK1 (ASK1-Delta N) in keratinocytes induced significant morphological changes and differentiation markers, transglutaminase-1, loricrin, and involucrin. A transient increase in p21Cip1/WAF1 reduced DNA synthesis, and cell cycle analysis verified the differentiation. p38 MAP kinase inhibitors, SB202190 and SB203580, abolished the induction of differentiation markers, transglutaminase-1, loricrin, and involucrin. In turn, the induction of differentiation with ceramide in keratinocytes caused an increase in ASK1 expression and activity. Furthermore, normal human skin expresses ASK1 protein in the upper epidermis, implicating ASK1 in in vivo keratinocyte differentiation. We propose that the ASK1-p38 MAP kinase cascade is a new intracellular regulator of keratinocyte differentiation.

* This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan and a SHISEIDO Grant for Skin Aging Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Dermatology, Ehime University School of Medicine, Shigenobucho, Onsengun, Ehime 791-0295, Japan. Tel.: 81 (89) 960-5350; Fax:. 81 (89) 960-5352; E-mail: sayama@m.ehime-u.ac.jp.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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