Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition
Autor: | Anthony DeBlasio, Zhen Fan, Yang Lu, Xipu Wu, Andrew Koff, John Mendelsohn |
---|---|
Rok vydání: | 1995 |
Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Protein Serine-Threonine Kinases Receptor tyrosine kinase chemistry.chemical_compound Phenols Epidermal growth factor Cyclins Proliferating Cell Nuclear Antigen Nitriles CDC2-CDC28 Kinases Tumor Cells Cultured Humans Epidermal growth factor receptor Enzyme Inhibitors neoplasms Epidermal Growth Factor biology Cell growth Cell Cycle Cyclin-Dependent Kinase 2 Articles Cell Biology Protein-Tyrosine Kinases Tyrphostins Cyclin-Dependent Kinases Growth Inhibitors Cell biology ErbB Receptors chemistry Cell culture Carcinoma Squamous Cell biology.protein biological phenomena cell phenomena and immunity Growth inhibition Signal transduction A431 cells hormones hormone substitutes and hormone antagonists Signal Transduction |
Zdroj: | The Journal of Cell Biology |
ISSN: | 1540-8140 0021-9525 |
DOI: | 10.1083/jcb.131.1.235 |
Popis: | Proliferation of some cultured human tumor cell lines bearing high numbers of epidermal growth factor (EGF) receptors is paradoxically inhibited by EGF in nanomolar concentrations. In the present study, we have investigated the biochemical mechanism of growth inhibition in A431 human squamous carcinoma cells exposed to exogenous EGF. In parallel, we studied a selected subpopulation, A431-F, which is resistant to EGF-mediated growth inhibition. We observed a marked reduction in cyclin-dependent kinase-2 (CDK2) activity when A431 and A431-F cells were cultured with 20 nM EGF for 4 h. After further continuous exposure of A431 cells to EGF, the CDK2 activity remained at a low level and was accompanied by persistent G1 arrest. In contrast, the early reduced CDK2 activity and G1 accumulation in A431-F cells was only transient. We found that, at early time points (4-8 h), EGF induces p21Cip1/WAF1 mRNA and protein expression in both EGF-sensitive A431 cells and EGF-resistant A431-F cells. But only in A431 cells, was p21Cip1/WAF1 expression sustained at a significantly increased level for up to 5 d after addition of EGF. Induction of p21Cip1/WAF1 by EGF could be inhibited by a specific EGF receptor tyrosine kinase inhibitor, tyrphostin AG1478, suggesting that p21Cip1/WAF1 induction was a consequence of receptor tyrosine kinase activation by EGF. We also demonstrated that the increased p21Cip1/WAF1 was associated with both CDK2 and proliferating cell nuclear antigen (PCNA). Taken together, our results demonstrate that p21Cip1/WAF1 is an important mediator of EGF-induced G1 arrest and growth inhibition in A431 cells. |
Databáze: | OpenAIRE |
Externí odkaz: |