FIGURE 2

IKK and JNK1 inversely control hepatocyte survival and compensatory proliferation in DEN-treated mice. DEN undergoes metabolic activation in zone 3 hepatocytes resulting in accumulation of ROS, which exert a cytotoxic effect that may be due to sustained JNK activation. DEN can also lead to necrotic cell death through induction of DNA damage and also causes IKK and JNK activation through unknown mechamisms. Activation of NF-B promotes cell survival through different mechamisms, including the upregulation of anti-oxidants, such as SOD2 and FHC that prevent excessive ROS accumulation and prolonged JNK activation, and induction of anti-apoptotic proteins, such as c-FLIP and Bcl-X_L. Insufficient activation of NF-B promotes ROS accumulation, leading to sustained JNK activation and cell death. In addition to its role in cell death, JNK can activate AP-1 transcription factors and enhance cyclin D expression, thereby promoting the proliferation of surviving hepatocytes.