In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 39 ( 2005-09-27), p. 13921-13926
Abstract:
Growth suppression of normal human keratinocytes by high Ca 2 + or TGFβ was shown to be mediated by p21 WAF1/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 Ca 2+ 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 p21 WAF1/CIP1 through activation of Sp1/Sp3. In the present study, we found that high Ca 2+ 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 p21 WAF1/CIP1 . Sp1 complexed with NFAT1 in high Ca 2+ -treated cells or with Smad3 in TGFβ1-treated cells, but not Sp1 alone, replaced KLF16 from the p21 WAF1/CIP1 promoter and transcriptionally activated the p21 WAF1/CIP1 gene. Thus, high Ca 2+ and TGFβ1 have a common S100C/A11-mediated pathway in addition to a unique pathway (NFAT1-mediated pathway for high Ca 2+ 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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0500630102
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2005
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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