Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells
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Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells. We previously reported that the FrbB2 oncoprotein prolongs and amplifies growth factor signalling by impairing ligand- dependent downregulation of hetero-oligomerised epidermal growth factor receptors. Here we show that treatment of A431 cells with different epidermal growth factor receptor ligands can cause growth inhibition to an extent paralleling ErbB2 tyrosine phosphorylation. To determine whether such growth inhibition signifies an interaction between the cell cycle machinery and b ErbB2-dependent alterations of cell signalling kinetics, we used MCF7 breast cancer cells (which express wild- type p53) to create transient and stable ErbB2 transfectants (MCF-B2). Compared with parental cells, MCF7-B2 cells are characterised by upregulation of p53, P21(WAF) and Myc, downregulation of Bcl2, and apoptosis. In contrast, MCF-B2 cells co-transfected with dominant negative p53 (MCF7- B2/Deltap53) exhibit reduced apoptosis and enhanced growth relative to both parental MCF7-B2 and control cells, These data imply that wild-type p53 limits survival of ErbB2- overexpressing breast cancer cells, and suggest b b that signals of varying length and/or intensity may evolve different cell outcomes depending upon the integrity of cell cycle control genes. We submit that acquisition of cell cycle control defects may play a permissive role in ErbB2 upregulation, and that the FrbB2 overexpression phenotype may in turn select for the survival of cells with p53 mutations or other tumour suppressor gene defects.
ErbB2 p53 apoptosis WILD-TYPE P53 MYC-INDUCED APOPTOSIS FACTOR RECEPTOR DOWN- REGULATION EPITHELIAL-CELLS EGF-RECEPTOR MAP KINASE A431 CELLS MUTANT P53 TYROSINE PHOSPHORYLATION
Signal Transduction & Molecular Pharmacology
Target Evaluation and Molecular Therapeutics
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BRITISH JOURNAL OF CANCER, 2002, 86 (7), pp. 1104 - 1109