The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnk genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.

The c-Jun NH(2)-terminal kinase (JNK) can cause cell death by activating the mitochondrial apoptosis pathway. However, JNK is also capable of signaling cell survival. The mechanism that accounts for the dual role of JNK in apoptosis and survival signaling has not been established. Here we demonstrate that JNK-stimulated survival signaling can be mediated by JunD. The JNK/JunD pathway can collaborate with NF-kappaB to increase antiapoptotic gene expression. This observation accounts for the ability of JNK to cause either survival or apoptosis in different cellular contexts. Furthermore, these data illustrate the general principal that signal transduction pathway integration is critical for the ability of cells to mount an appropriate biological response to a specific challenge.

The c-Jun NH(2)-terminal kinase (JNK) is implicated in the apoptotic response of cells exposed to stress, but the JNK signal transduction pathway may not act exclusively in apoptosis. In some studies of tumor cells, JNK has been implicated in signaling cell survival. The possibility that JNK might mediate a survival signal in tumor cells is consistent with the observation that it is activated in response to some oncogenes, such as the leukemogenic oncogene BCR-ABL, which is created by a reciprocal translocation between human chromosomes 9 and 22 (ref. 2). The BCR-ABL protein activates the JNK signaling pathway in hematopoietic cells and increases transcriptional activity mediated by the transcription factor AP1 (ref. 3). Also, inhibition of c-Jun or JNK prevents BCR-ABL-induced cell transformation in vitro. Although this implicates the JNK signaling pathway in transformation by BCR-ABL, the possible role of JNK in this process is unclear. We find that disruption of the JNK ortholog Mapk8 (also known as Jnk1) in mice causes defective transformation of pre-B cells by BCR-ABL in vitro and in vivo. The Jnk1 protein is required for the survival of the transformed cells in the absence of stromal support. Failure to survive is associated with decreased expression of Bcl2, and the effect of Jnk1 deficiency can be rescued by transgenic expression of Bcl2. Our results show that Jnk1 signals cell survival in transformed B lymphoblasts and suggest that it may contribute to the pathogenesis of some proliferative diseases.