Phosphatidylinositol 3-kinase regulates early differentiation in human laryngeal keratinocytes |
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Authors: | Raduwan Dackour Timothy Carter Bettie M Steinberg |
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Institution: | (1) Institute for Medical Research, North Shore-LIJ Health System and Department of Otolaryngology, Long Island Jewish Medical Center, 11040 New Hyde Park, New York;(2) Department of Biological Sciences, St. John's University, USA |
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Abstract: | Summary Epidermal growth factor receptor (EGFR) signaling regulates a variety of cellular functions, including proliferation, gene
expression, and differentiation. Infection of laryngeal epithelial cells by human papillomaviruses causes recurrent respiratory
papillomas, benign tumors characterized by an altered pattern of differentiation. Papilloma cells overexpress the EGFR and
have constitutively active extracellular signal-regulated kinase (ERK) and enhanced phosphatidylinositol 3-kinase (PI3K) activity,
but overexpression of the lipid phosphatase PTEN (Phosphatase and Tensin Homolog) reduces activation of Akt by PI3K. We hypothesized
that the altered differentiation of papillomas reflects these changes in signaling from the EGFR-ERK and PI3K-Akt pathways
and that one or both of these pathways is required for the normal differentiation process in mucosal epithelium. Inhibiting
either the enzymatic activity or the synthesis of PI3K in uninfected laryngeal cells blocked expression of keratin-13 (K13),
a protein induced during normal differentiation. In contrast, inhibiting activation of ERK had minimal effect. Using ribonucleic
acid interference to reduce protein levels of integrinlinked kinase 1 or phosphoinositide-dependent protein kinase 1, intermediates
in the activation of Akt by PI3K, or reducing levels of Akt-1 itself did not inhibit K13 expression by normal laryngeal keratinocytes.
We conclude that PI3K activation is an important regulator of expression of K13, a marker for the normal differntiation process
in human mucosal keratinocytes, that this function does not require activation of Akt-1, and that the failure to express K13
in papilloma cells is not because of reduction in activated Akt. |
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Keywords: | human papillomavirus ERK Akt signal transduction |
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