The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development.
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.
Sibilia
M
M
Research Institute of Molecular Pathology, Vienna, Austria. maria.sibilia@univie.ac.at
Fleischmann
A
A
Behrens
A
A
Stingl
L
L
Carroll
J
J
Watt
F M
FM
Schlessinger
J
J
Wagner
E F
EF
D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010212:Papilloma / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism*; D020664:Son of Sevenless Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D020664:Son of Sevenless Proteins; D066246:ErbB Receptors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins