Abstract
Growth regulation of epithelial cells is of major concern because most human cancers arise from them. We demonstrated previously a novel signal pathway involving S100C/A11 for high Ca2+-induced growth inhibition of normal human keratinocytes (Sakaguchi, M., M. Miyazaki, M. Takaishi, Y. Sakaguchi, E. Makino, N. Kataoka, H. Yamada, M. Namba, and N.H. Huh. 2003. J. Cell Biol. 163:825-835). This paper addresses a question whether transforming growth factor beta (TGFbeta) shares the pathway with high Ca2+. On exposure of the cells to TGFbeta1, S100C/A11 was phosphorylated, bound to nucleolin, and transferred to the nucleus, resulting in induction of p21WAF1/CIP1 and p15INK4B through activation of Sp1. Protein kinase C alpha (PKCalpha) was shown to phosphorylate 10Thr of S100C/A11, which is a critical event for the signal transduction. The TGFbeta1-induced growth inhibition was almost completely mitigated when PKCalpha activity was blocked or when S100C/A11 was functionally sequestered. These results indicate that, in addition to the well-characterized Smad-mediated pathway, the PKCalpha-S100C/A11-mediated pathway is involved in and essential for the growth inhibition of normal human keratinocytes cells by TGFbeta1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle Proteins / metabolism
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Cell Division / drug effects*
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Cell Line
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Nucleus / ultrastructure
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / physiology
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Humans
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Keratinocytes / cytology*
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Keratinocytes / drug effects
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Keratinocytes / physiology
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Nucleolin
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Kinase C / metabolism*
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Protein Kinase C-alpha
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Protein Transport
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RNA-Binding Proteins / metabolism
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S100 Proteins / drug effects
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S100 Proteins / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transforming Growth Factor beta / pharmacology*
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Tumor Suppressor Proteins / metabolism
Substances
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CDKN1A protein, human
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CDKN2B protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Phosphoproteins
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RNA-Binding Proteins
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S100 Proteins
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Transforming Growth Factor beta
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Tumor Suppressor Proteins
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S100A11 protein, human
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PRKCA protein, human
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Protein Kinase C
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Protein Kinase C-alpha