Abstract
Fas-mediated cell death was examined in MCF-10AT preneoplastic human breast epithelial cells. Treatment with anti-Fas for 48 h induced apoptosis with cells exhibiting typical apoptotic features including loss of cell contact, condensation of chromatin, and increased staining of the nuclear membrane. DNA fragmentation occurred in response to anti-Fas treatment. Anti-Fas treatment resulted in decreased p53 protein levels, while bcl-2 and bax protein levels remained unaffected. Cells treated with anti-Fas also exhibited increased tyrosine phosphorylation of the c-met growth factor receptor tyrosine kinase. Immunoprecipitation experiments demonstrated that Fas associated with c-erbB2 and c-met in untreated cells. Treatment with anti-Fas, however, significantly decreased Fas-c-erbB2 and Fas-c-met association. Anti-Fas treatment of these cells caused a significant decrease in p120-GAP levels, ERK-1 levels, and phosphorylation, as well as Grb2-Sosl and MEK-1-ERK-1 association. These results show that Fas-signaling exerted a suppressive effect on p53 levels and on downstream effectors of receptor tyrosine kinase signal transduction, thereby ensuring cell death.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Antibodies / pharmacology
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Apoptosis*
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Breast / cytology
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Breast / physiology*
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Breast Neoplasms / pathology*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Line
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Chromatin / ultrastructure
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Epithelial Cells
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Epithelium / physiology
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Female
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Fungal Proteins / metabolism
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GRB2 Adaptor Protein
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GTPase-Activating Proteins
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Humans
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MAP Kinase Kinase 1
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases*
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Mitogen-Activated Protein Kinases*
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Nuclear Envelope / ultrastructure
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Phosphorylation
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Precancerous Conditions / pathology*
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-met
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor, ErbB-2 / metabolism
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Repressor Proteins / metabolism
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SOS1 Protein
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Signal Transduction*
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Transplantation, Heterologous
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bcl-2-Associated X Protein
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fas Receptor / immunology
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fas Receptor / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies
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BAX protein, human
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Bax protein, mouse
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Chromatin
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Fungal Proteins
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GRB2 Adaptor Protein
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GRB2 protein, human
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GTPase-Activating Proteins
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Grb2 protein, mouse
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Repressor Proteins
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SOS1 Protein
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bcl-2-Associated X Protein
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fas Receptor
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-met
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Receptor Protein-Tyrosine Kinases
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Receptor, ErbB-2
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Map2k1 protein, mouse
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Mitogen-Activated Protein Kinase Kinases