Increased expression of Mcl-1 is responsible for the blockage of TRAIL-induced apoptosis mediated by EGF/ErbB1 signaling pathway.
Epidermal growth factor (EGF) protects against death receptor induced apoptosis in epithelial cells. Herein, we demonstrate that EGF protection against tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced apoptosis is mediated by increased expression of the Bcl-2 family member myeloid cell leukemia 1 (Mcl-1). EGF increased the mRNA and protein levels of Mcl-1. Furthermore, expression of ErbB1 alone or in combination with ErbB2 in NIH3T3 cells up-regulates Mcl-1 following EGF treatment. In addition, up-regulation of Mcl-1 by EGF is mediated through AKT and NFkappaB activation since kinase inactive AKT and DeltaIkappaB effectively blocks this up-regulation. NFkappaB was also critical for the ability of EGF to prevent TRAIL induced apoptosis as a dominant negative IkappaB (DeltaIkappaB) blocked NFkappaB activation, and relieved EGF protection against TRAIL mediated mitochondrial cytochrome-c release and apoptosis. Finally, anti-sense oligonucleotides directed against Mcl-1 effectively reduced the protein levels of Mcl-1 and blocked EGF protection against TRAIL induced mitochondrial cytochrome-c release and apoptosis. Taken together, EGF signaling leads to increased Mcl-1 expression that is required for blockage of TRAIL induced apoptosis.
Henson
Elizabeth S
ES
Manitoba Institute of Cell Biology, University of Manitoba, 675 McDermot Ave., Winnipeg, Manitoba, R3E 0V9.
Gibson
Erika M
EM
Villanueva
Jacylyn
J
Bristow
Nicolle A
NA
Haney
Neil
N
Gibson
Spencer B
SB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D018773:Genes, erbB-1 / Q000502:physiology; D018734:Genes, erbB-2 / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C579094:Mcl1 protein, mouse; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D045304:Cytochromes c