The level of tyrosine kinase activity regulates the expression of p21/WAF1 in cancer cells

Int J Oncol. 1999 Aug;15(2):301-6. doi: 10.3892/ijo.15.2.301.


It is well documented that epidermal growth factor (EGF) inhibits proliferation of A431 and MDA-468 cells via activation of p21/WAF1. In the present study, we have shown that treatment of MDA-468 and A431 cells that express high levels of EGFR with 100 ng/ml of EGF leads to 14.9-fold increase in epidermal growth factor receptor (EGFR) autophosphorylation and high levels of p21/WAF1-induction (6. 7-fold), down regulation of cdk2 activity and growth arrest. When MDA-468 or A431 cells were simultaneously treated with 100 ng/ml EGF and RG13022, a relatively specific tyrosine kinase inhibitor, there was a significant reduction in p21/WAF1 levels. In contrast, when MDA-468, A432 cells that are treated with low levels of EGF (10 ng/ml) or other cells which express low to moderate levels of EGFRs such as MCF-7, MCF-10A, MDA-231 and SKBR-3 breast cells were exposed to 100 ng/ml of EGF there was a 3.8-fold increase in EGFR autophosphorylation, leading to 1.6-fold induction of p21/WAF1 and increased cell proliferation. These results suggest that the level of EGFR tyrosine kinase activity may regulate p21/WAF1 induction in cancer cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis*
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / metabolism*
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • Humans
  • Neoplasm Proteins / biosynthesis*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism*
  • STAT1 Transcription Factor
  • Signal Transduction / drug effects
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Epidermal Growth Factor
  • ErbB Receptors
  • Protein-Tyrosine Kinases