Fas-signaling and effects on receptor tyrosine kinase signal transduction in human breast epithelial cells.
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.
Shen
K
K
Institute of Chemical Toxicology and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
Novak
R F
RF
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D001940:Breast / Q000166:cytology / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000648:ultrastructure; D004847:Epithelial Cells; D004848:Epithelium / Q000502:physiology; D005260:Female; D005656:Fungal Proteins / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D020690:GTPase-Activating Proteins; D006801:Humans; D048369:MAP Kinase Kinase 1; D051379:Mice; D008819:Mice, Nude; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009685:Nuclear Envelope / Q000648:ultrastructure; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020837:SOS1 Protein; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002843:Chromatin; D005656:Fungal Proteins; D051380:GRB2 Adaptor Protein; D020690:GTPase-Activating Proteins; D048369:MAP Kinase Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D012097:Repressor Proteins; D020837:SOS1 Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C494826:BAX protein, human; C494827:Bax protein, mouse; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse