JNK activation is required for JB6 cell transformation induced by tumor necrosis factor-α but not by 12-O-tetradecanoylphorbol-13-acetate

Signal transduction via mitogen-activated protein kinase pathways plays a key role in a variety of cellular responses, including cell proliferation, differentiation, tumor promotion, and cell death, c-Jun N-terminal kinases (JNKs) are identified as members of the mitogen-activated protein kinase family and are known to phosphorylate and activate several transcription factors, including c-Jun, ATF, and Elk-1. However, the role of JNK activation in tumor promotion is not yet defined. Because previous studies have indicated that exposure of JB6 Cl 41 cells to either 12-O- tetradecanoylphorbol-13-acetate (TPA) or tumor necrosis factor-α (TNF-α) results in cell transformation, we investigated the role of JNKs in this biological process by using dominant negative JNK₁ and the cell transformation model JB6 Cl 41 cells. Incubation of Cl 41 cells with TNF-α led to cell transformation and activation of JNKs. Introduction of the dominant negative mutant of JNK₁ into JB6 Cl 41 cells specifically inhibited TNF-α-induced activation of JNKs, but not Erks and p38 kinases. Most importantly, expressing dominant negative mutant JNK₁ inhibited TNF-α- induced cell transformation but not TPA-induced cell transformation, our results directly demonstrated for the first time that JNK activation is required for TNF-α- but not TPA-induced cell transformation.