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Published online 17 November 2003. doi:10.1083/jcb.200304017
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© The Rockefeller University Press, 0021-9525/2003/11/825 $8.00
The Journal of Cell Biology, Volume 163, Number 4, 825-835

Article

 S100C/A11 is a key mediator of Ca2+-induced growth inhibition of human epidermal keratinocytes

Masakiyo Sakaguchi1, Masahiro Miyazaki1, Mikiro Takaishi1, Yoshihiko Sakaguchi2, Eiichi Makino3, Noriyuki Kataoka4, Hidenori Yamada5, Masayoshi Namba6 and Nam-ho Huh1

1 Department of Cell Biology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
2 Department of Bacteriology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
3 Department of Dermatology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
4 Department of Medical Engineering, Kawasaki Medical School, Okayama 701-0192, Japan
5 Department of Bioscience and Biotechnology, Okayama University Graduate School of Natural Science and Technology, Okayama 700-8530, Japan
6 Niimi College, Niimi 718-8585, Japan

Address correspondence to Nam-ho Huh, Dept. of Cell Biology, Okayama University Graduate School of Medicine and Dentistry, Shikata-chou, Okayama 700-8558, Japan. Tel.: 81-86-235-7393. Fax: 81-86-235-7400. email: namu{at}md.okayama-u.ac.jp

An increase in extracellular Ca2+ induces growth arrest and differentiation of human keratinocytes in culture. We examined possible involvement of S100C/A11 in this growth regulation. On exposure of the cells to high Ca2+, S100C/A11 was specifically phosphorylated at 10Thr and 94Ser. Phosphorylation facilitated the binding of S100C/A11 to nucleolin, resulting in nuclear translocation of S100C/A11. In nuclei, S100C/A11 liberated Sp1/3 from nucleolin. The resulting free Sp1/3 transcriptionally activated p21CIP1/WAF1, a representative negative regulator of cell growth. Introduction of anti-S100C/A11 antibody into the cells largely abolished the growth inhibition induced by Ca2+ and the induction of p21CIP1/WAF1. In the human epidermis, S100C/A11 was detected in nuclei of differentiating cells in the suprabasal layers, but not in nuclei of proliferating cells in the basal layer. These results indicate that S100C/A11 is a key mediator of the Ca2+-induced growth inhibition of human keratinocytes in culture, and that it may be possibly involved in the growth regulation in vivo as well.

Key Words: keratinocyte; calcium; Sp1; nucleolin; p21CIP1/WAF1

The online version of this article includes supplemental material.

Abbreviations used in this paper: NHK, normal human keratinocyte; PEI, polyethyleneimine; siRNA, small interfering RNA.


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