THE BCR-ABL LEUKEMIA ONCOGENE ACTIVATES JUN KINASE AND REQUIRES JUN FOR TRANSFORMATION

The leukemogenic tyrosine kinase fusion protein Bcr-Abl activates a Ras dependent pathway required for transformation, To examine subsequent signal transduction events we measured the effect of Bcr-Abl on two mitogen-activated protein kinase (MAPK) cascades-the extracellular signal-regulated kinase (ERK) pathway and the Jun N-terminal kinase (JNK) pathway, We find that Bcr-Abl primarily activates JNL in fibroblasts and hematopoietic cells, Bcr-Abl enhances JNK function as measured by transcription from Jun responsive promoters and requires Ras, MEK kinase (MAPK/ERK kinase kinase), and JNK to do so. Dominant-negative mutants of c-Jun, which inhibit the endpoint of the JNK pathway, impair Bcr-Abl transforming activity, These findings implicate the JNK pathway in transformation by a human leukemia oncogene.