Abstract
The EGF receptor (EGFR) is required for skin development and is implicated in epithelial tumor formation. Transgenic mice expressing a dominant form of Son of Sevenless (SOS-F) in basal keratinocytes develop skin papillomas with 100% penetrance. However, tumor formation is inhibited in a hypomorphic (wa2) and null EGFR background. Similarly, EGFR-deficient fibroblasts are resistant to transformation by SOS-F and rasV12, however, tumorigenicity is restored by expression of the anti-apoptotic bcl-2 gene. The K5-SOS-F papillomas and primary keratinocytesfrom wa2 mice display increased apoptosis, reduced Akt phosphorylation and grafting experiments imply a cell-autonomous requirement for EGFR in keratinocytes. Therefore, EGFR functions as a survival factor in oncogenic transformation and provides a valuable target for therapeutic intervention in a broader range of tumors than anticipated.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Cell Transformation, Neoplastic
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Cells, Cultured
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Fibroblasts / cytology
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Humans
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Keratinocytes / cytology
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Mice
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Mice, Inbred C57BL
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Mice, Inbred CBA
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Mice, Nude
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Papilloma / metabolism*
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction*
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Skin Neoplasms / metabolism*
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Son of Sevenless Proteins / genetics
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Son of Sevenless Proteins / metabolism*
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ras Proteins / metabolism
Substances
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Proto-Oncogene Proteins
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Son of Sevenless Proteins
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ErbB Receptors
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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ras Proteins