Abstract
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 Ca(2+)-induced growth inhibition of human keratinocytes in culture, and that it may be possibly involved in the growth regulation in vivo as well.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / physiology
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Animals
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Antibodies / pharmacology
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Binding, Competitive / physiology
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Calcium / metabolism
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Calcium / pharmacology
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Calcium Signaling / physiology*
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Division / drug effects
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Cell Division / physiology
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Cell Line, Transformed
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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Epidermal Cells
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Epidermis / growth & development*
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Epidermis / metabolism
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Extracellular Fluid / drug effects
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Extracellular Fluid / metabolism
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Humans
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Keratinocytes / cytology
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Keratinocytes / drug effects
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Keratinocytes / metabolism*
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Nucleolin
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Binding / physiology
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RNA-Binding Proteins / metabolism
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S100 Proteins / metabolism*
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Sp1 Transcription Factor / metabolism
Substances
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Antibodies
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CDKN1A protein, human
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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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Sp1 Transcription Factor
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S100A11 protein, human
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Calcium