The level of tyrosine kinase activity regulates the expression of p21/WAF1 in cancer cells.
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.
Department of Pathology, Wayne State University, Detroit, MI 48201, USA.
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Reddy
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Keshamouni
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Chen
D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases