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The survival and growth of epithelial cells depends on adhesion to the extracellular matrix. An adhesion signal may regulate the initiation of differentiation, since epidermal keratinocytes differentiate as they leave the basement membrane. A metabolically dead cornified cell envelope is the end point of epidermal differentiation so that this process may be viewed as a specialized form of programmed cell death. In order to investigate the precise cellular signaling events leading to terminal differentiation of keratinocytes, we have utilized HaCaT cells to monitor the biological consequences of Ca²? stimulation and numerous downstream signaling pathways, including activation of the extracellular signal-regulated protein kinase (ERK) pathway and activation of phosphatidylinositol 3-kinase (PI3K). The results presented in this study show that Ca²? function as potent agents for the differentiation of HaCaT keratinocytes, and this differentiation depends on the activation of ERK, Protein kinase B (PKB) and p70 ribosomal protein S6 kinase (p70S6K). Finally, the results show that the expression of Activator protein 1 (AP-1; c-Jun and c-Fos) increased following Ca²?-mediated differentiation of HaCaT cells, suggesting that ERK-mediated AP-1 expression is critical for initiating the terminal differentiation of keratinocytes.

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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENTS
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UCI(KEPA) : I410-ECN-0101-2009-513-017426730