34 Thus, JNK1 and JNK2 have a wide range and redundant

or distinct functions, and upstream molecules, such as MAP3Ks, must regulate the complex functions of JNK. We consider that ASK1 plays major roles in tumor-suppressing CAL-101 part of JNK in hepatocarcinogenesis. However, knockdown of ASK1 in HCC cell lines slightly decreased cell proliferation. This finding suggests that ASK1 may weakly promote the proliferation of some HCC cells, which could explain why the WT and ASK1−/− mice did not exhibit significant differences in tumor size. On the other hand, mice with liver-specific p38 deficiency exhibit increased HCC development similar to ASK1−/− mice.4, 6 The accelerated hepatocarcinogenesis in p38-deficient mice is reportedly attributable to compensatory

JNK activation and cancer cell proliferation. Although p38 activation was attenuated in ASK1−/− mice, JNK activation was also attenuated, unlike the liver-specific p38-deficient mice. Thus, the mechanisms of accelerated hepatocarcinogenesis in ASK1−/− mice and liver- specific p38-deficient mice appear to differ. p38 has also been reported to play IWR-1 solubility dmso an important role in DNA damage responses, such as cellular senescence, by inducing cyclin-dependent kinase inhibitors.30 In this study, we showed that ASK1 is involved in DNA damage-induced p21 up-regulation through p38 activation. Furthermore, the ASK1-p38 pathway has been reported to have an inhibitory effect on malignant transformation of fibroblasts by triggering apoptosis in response to oncogene-induced reactive oxygen species (ROS).35 Thus, the ASK1-p38 pathway may play a key role in the inhibition of tumor initiation in hepatocarcinogenesis. Defective death-receptor signaling is considered a cause of tumor immune escape, so understanding its apoptotic mechanism is very important not only from the point of view of carcinogenesis, but also

for cancer therapeutics.21 Several in vitro studies have demonstrated that ASK1 is implicated in the TNF-α- and Fas-mediated apoptotic pathways,11, 上海皓元医药股份有限公司 36 but the in vivo role of ASK1 has not been determined. Our current findings provide the first evidence that ASK1 plays an important role in TNF-α- and Fas-mediated hepatocyte apoptosis in vivo and suggest that the JNK- Bim-mediated mitochondrial apoptotic pathway is an important downstream target of ASK1. JNK-mediated Bim phosphorylation triggers the proapoptotic activity of Bim by causing its release from sequestration to the microtubular dynein motor complex.25 Bim initiates the mitochondrial apoptotic pathway by activating Bax and Bak directly and indirectly blocking prosurvival Bcl-2 family members.37 Recent reports have shown that Bim plays an important role in Fas- and TNF-α-induced hepatocyte apoptosis.