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J. Biol. Chem., Vol. 281, Issue 31, 22013-22020, August 4, 2006

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Transforming Growth Factor--activated Kinase 1 Is Essential for Differentiation and the Prevention of Apoptosis in Epidermis^*

Koji Sayama¹, Yasushi Hanakawa, Hiroshi Nagai, Yuji Shirakata, Xiuju Dai, Satoshi Hirakawa, Sho Tokumaru, Mikiko Tohyama, Lujun Yang, Shintaro Sato, Akira Shizuo, and Koji Hashimoto

From the Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295 and the Research Institute for Microbial Disease, Osaka University, Suita 565-0871, Japan

Transforming growth factor--activated kinase 1 (TAK1) is a member of the mitogen-activated protein (MAP) kinase family and is an upstream signaling molecule of nuclear factor-B (NF-B). Given that NF-B regulates keratinocyte differentiation and apoptosis, TAK1 may be essential for epidermal functions. To test this, we generated keratinocyte-specific TAK1-deficient mice from Map3k7^flox/flox mice and K5-Cre mice. The keratinocyte-specific TAK1-deficient mice were macroscopically indistinguishable from their littermates until postnatal day 2 or 3, when the skin started to roughen and wrinkle. This phenotype progressed, and the mice died by postnatal day 7. Histological analysis showed thickening of the epidermis with foci of keratinocyte apoptosis and intra-epidermal micro-abscesses. Immunohistochemical analysis showed that the suprabasal keratinocytes of the TAK1-deficient epidermis expressed keratin 5 and keratin 14, which are normally confined to the basal layer. The expression of keratin 1, keratin 10, and loricrin, which are markers for the suprabasal and late phase differentiation of the epidermis, was absent from the TAK1-deficient epidermis. Furthermore, the TAK1-deficient epidermis expressed keratin 16 and had an increased number of Ki67-positive cells. These data indicate that TAK1 deficiency in keratinocytes results in abnormal differentiation, increased proliferation, and apoptosis in the epidermis. However, the keratinocytes from the TAK1-deficient epidermis induced keratin 1 in suspension culture, indicating that the TAK1-deficient keratinocytes retain the ability to differentiate. Moreover, the removal of TAK1 from cultured keratinocytes of Map3k7^flox/flox mice resulted in apoptosis, indicating that TAK1 is essential for preventing apoptosis. In conclusion, TAK1 is essential in the regulation of keratinocyte growth, differentiation, and apoptosis.

Received for publication, February 3, 2006 , and in revised form, April 17, 2006.

^* This work was supported by grants from the Ministries of Health, Labor, and Welfare and Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Dermatology, Ehime University School of Medicine, Toon, Ehime, 791-0295, Japan. Tel.: 81-89-960-5350; Fax: 81-89-960-5350; E-mail: sayama{at}m.ehime-u.ac.jp.

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