Suppression of Ras-stimulated transformation by the JNK signal transduction pathway

The c-jun NH2-terminal kinase (JNK) phosphorylates and activates members of the activator protein-1 (AP-1) group of transcription factors and is implicated in oncogenic transformation. To examine the role of INK, we investigated the effect of INK deficiency on Ras-stimulated transformation. We demonstrate that although INK does play a role in transformation in vitro, INK is not required for tumor development in vivo. Importantly, the loss of INK expression resulted in substantial increases in the number and growth of tumor nodules in vivo. Complementation assays demonstrated that this phenotype was caused by INK deficiency. These data demonstrate that, in contrast to expectations, the normal function of INK may be to suppress tumor development in vivo. This conclusion is consistent with the presence in human tumors of loss-of-function mutations in the INK pathway.