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J. Biol. Chem., Vol. 279, Issue 48, 50069-50077, November 26, 2004

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p51/p63 Controls Subunit ₃ of the Major Epidermis Integrin Anchoring the Stem Cells to the Niche^*

Shun-ichi Kurata, Takeshi Okuyama¶, Motonobu Osada||**, Tatsuya Watanabe¶, Yoshiya Tomimori, Shingo Sato, Aki Iwai, Tsutomu Tsuji||||, Yoji Ikawa, and Iyoko Katoh¶¶

From the Department of Biochemical Genetics, Medical Research Institute, ^||Human Gene Sciences Center, Graduate School of Allied Health Sciences, Department of Immune Regulation, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 Japan, the Ikawa Laboratory, RIKEN, The Institute of Physical and Chemical Research, 2-1 Hirosawa, Wako, Saitama 351-0198 Japan, the ^¶Department of Molecular Physiology, Kyoritsu College of Pharmacy, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512 Japan, and the ^||||Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan

p51/p63, a member of the tumor suppressor p53 gene family, is crucial for skin development. We describe here identification of ITGA3 encoding integrin ₃ as a target of its trans-activating function, proposing that p51/p63 allows epidermal stem cells to express laminin receptor ₃₁ for anchorage to the basement membrane. When activated by genotoxic stress or overexpressed ectopically in non-adherent cells, p51/p63 transduced a phenotype to attach to extracellular matrices, which was accompanied by expression of ITGA3. Motifs matching the p53-binding consensus sequence were located in a scattered form in intron 1 of human ITGA3, and served as p51/p63-responsive elements in reporter assays. In addition to the trans-activating ability of the TA isoform, we detected a positive effect of the N isoform on ITGA3. The high level ₃ production in human keratinocyte stem cells diminished upon elimination of p51/p63 by small interfering RNA or by Ca²⁺-induced differentiation. Furthermore, a chromatin immunoprecipitation experiment indicated a physical interaction of p51/p63 with intron 1 of ITGA3. This study provides a molecular basis for the standing hypothesis that p51/p63 is essential for epidermal-mesenchymal interactions.

Received for publication, June 7, 2004 , and in revised form, August 30, 2004.

^* This work was supported by grants-in-aid for Scientific Research on Priority Areas from the Ministry of 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.

^** Present address: Dept. of Otolaryngology Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

^¶¶ To whom correspondence should be addressed: Ikawa Laboratory, RIKEN, The Institute of Physical and Chemical Research, 2-1 Hirosawa, Wako, Saitama 351-0198 Japan. Tel.: 81-48-467-9789; Fax: 81-48-467-9790; E-mail: peace{at}postman.riken.jp.

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