Increased expression of Mcl-1 is responsible for the blockage of TRAIL-induced apoptosis mediated by EGF/ErbB1 signaling pathway

J Cell Biochem. 2003 Aug 15;89(6):1177-92. doi: 10.1002/jcb.10597.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Cytochromes c / metabolism
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Genes, erbB-1 / physiology
  • Genes, erbB-2 / physiology
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mitochondria / enzymology
  • Mitochondria / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NF-kappa B / metabolism
  • NIH 3T3 Cells
  • Neoplasm Proteins / biosynthesis*
  • Oligodeoxyribonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2*
  • Signal Transduction / physiology*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / metabolism*


  • Apoptosis Regulatory Proteins
  • Mcl1 protein, mouse
  • Membrane Glycoproteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NF-kappa B
  • Neoplasm Proteins
  • Oligodeoxyribonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Epidermal Growth Factor
  • Cytochromes c