Bifurcated converging pathways for high Ca2+- and TGFβ-induced inhibition of growth of normal human keratinocytes

Masakiyo Sakaguchi, Hiroyuki Sonegawa, Takamasa Nukui, Yoshihiko Sakaguchi, Masahiro Miyazaki, Masayoshi Namba, Nam Ho Huh


36 被引用数 (Scopus)


Growth suppression of normal human keratinocytes by high Ca2+ or TGFβ was shown to be mediated by p21WAF1/CIP1 and Sp1 [Pardali, K., et al. (2000) J. Biol. Chem. 275, 29244-29256; Santini, M. P., Talora, C., Seki, T., Bolgan, L. & Dotto, G. P. (2001) Proc. Nat. Acad. Sci. USA 98, 9575-9580; Al-Daraji, W. I., Grant, K. R., Ryan, K., Saxton, A., & Reynolds, N. J. (2002) J. Invest. Dermatol. 118, 779-788]. We previously demonstrated that S100C/A11 is a key mediator for growth inhibition of normal human epidermal keratinocytes (NHK) triggered by high Ca2+ or TGFβ [Sakaguchi, M., et al. (2003) J. Cell Biol. 163, 825-835; Sakaguchi, M., et al. (2004) 164, 979-984]. On exposure of NHK cells to either agent, S100C/A11 is transferred to nuclei, where it induces p21WAF1/CIP1 through activation of Sp1/Sp3. In the present study, we found that high Ca2+ activated NFAT1 through calcineurin-dependent dephosphorylation. In growing NHK cells, Krueppel-like factor (KLF)16, a member of the Sp/KLF family, bound to the p21 WAF1/CIP1 promoter and, thereby, inhibited the transcription of p21WAF1/CIP1. Sp1 complexed with NFAT1 in high Ca2+- treated cells or with Smad3 in TGFβ1-treated cells, but not Sp1 alone, replaced KLF16 from the p21WAF1/CIP1 promoter and transcriptionally activated the p21WAF1/CIP1 gene. Thus, high Ca2+ and TGFβ1 have a common S100C/A11-mediated pathway in addition to a unique pathway (NFAT1-mediated pathway for high Ca2+ and Smad-mediated pathway for TGFβ1) for exhibiting a growth inhibitory effect on NHK cells, and both pathways were shown to be indispensable for growth inhibition.

ジャーナルProceedings of the National Academy of Sciences of the United States of America
出版ステータスPublished - 9月 27 2005

ASJC Scopus subject areas

  • 一般


「Bifurcated converging pathways for high Ca2+- and TGFβ-induced inhibition of growth of normal human keratinocytes」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。