The c-Jun amino-terminal kinases (JNKs) belong to the mitogen-activated protein kinase family, and are involved in transducing mitogenic, inflammatory and stress signals in cells through the phosphorylation of transcription factors like c-Jun and ATF-2, which participate in the activation and formation of the activator-protein 1 (AP-1) transcriptional complex. 1 The JNK family consists of the three highly homologous members JNK1, JNK2 and JNK3. Among them, JNK3 is expressed predominantly in the brain whereas both JNK1 and JNK2 are expressed ubiquitously. 2 Combinatorial use of the various JNKs and their upstream kinases are thought to lead to differential regulation of substrate proteins in response to multiple stimuli, thereby establishing signal-specificity. Genetic analyzes using JNK knockout mice that we and others have generated have revealed specific roles for JNK1 and JNK2 in neuronal apoptosis, neuronal microtubules maintenance, T cell activation and apoptosis, acute liver inflammation and failure, regulation of insulin resistance and obesity, bile acid production, osteoclastogenesis, fibroblasts apoptosis and proliferation as well as tumorigenesis (reviewed in Ref. 2). Importantly, we have shown that JNK2 appears to be a negative regulator of fibroblast cellular proliferation in contrast to JNK1. 3 These findings together strongly suggest that the JNKs have both overlapping and distinct functions in different cell types.
Although JNK activity is often noted to be upregulated in cancers, 4 limited mouse model analysis have suggested that JNK1 and JNK2 may have opposing functions in regulating carcinogenesis. For example, 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin tumor development was found to be suppressed in Jnk2 À/À mice but enhanced in Jnk1 À/À mice. 5,6 In contrast, in a colitis model, loss of either JNK1 or JNK2 led to aggravation of dextran sodium sulfate (DSS)-induced colitis. 7 Besides these, not many studies have evaluated the specific roles of JNK1 or JNK2 in other models of carcinogenesis.
Activation of B cells have been shown to lead to JNK activation, 8 and the leukemogenic oncogene BCR-ABL has been demonstrated to activate the JNK signaling pathway and lead to the increase of AP-1 transcriptional activity. 9 Consistently, the inhibition of c-Jun or JNK prevents BCR-ABL-induced cell transformation in vitro. 10 Although this implicates the JNK signaling pathway in transformation by BCR-ABL, the Letter to the Editor