Oncogenic Neu/ErbB-2 Increases Ets, AP-1, and NF-kB-dependent Gene Expression, and Inhibiting Ets Activation Blocks Neu-mediated Cellular Transformation (*)

摘要: Overexpression of Neu (ErbB-2/HER2) is found in approximately 20% breast tumors. Activation by a point mutation (NeuT) causes constitutive tyrosine kinase activity this transmembrane receptor and transforming fibroblasts. To identify downstream targets Neu, we have analyzed the ability to activate gene expression. Expression NeuT, but not normal caused transcriptional activation Ets, AP-1, or NF-kappaB-dependent reporter genes. Dominant inhibitory Ras Raf mutants blocked Neu-mediated activation, confirming that signaling pathways were required for activation. Analysis with Ets2 indicated mediated NeuT oncogenic phosphorylation same residue, threonine 72. Cotransfection dominant specifically NeuT-mediated Ets-dependent Furthermore, focus formation assays using NIH 3T3 cells, was inhibited 5-fold when cotransfected negative mutant. However, parallel colony showed mutant did inhibit growth cells. Together, these data show activates variety transcription factor families via pathway Ets cellular transformation. Thus, including factors, may be useful points therapeutic intervention Neu/ErbB-2-associated cancers.