3 and Bettermann et al.4 have identified transforming growth factor (TGF) β-activated kinase 1 (TAK1) as an essential inhibitor of this fatal series of events in hepatocytes. TAK1 belongs to the mitogen-activated protein kinase kinase kinase (MAP3K) family and acts as a mediator of stress, apoptosis, and inflammatory signals in the liver. Upon ligand activation, Toll-like receptor/interleukin-1 receptor (TLR/IL1R) and tumor necrosis factor receptor (TNFR) recruit and phosphorylate TAK1 through TNFR-associated

factors (TRAFs). Phosphorylated TAK1 activates IκB kinase (IKK) and MAP kinase kinase 4/7 (MKK4/7), leading to the activation of nuclear factor-κ B (NF-κB) and c-Jun N-terminal kinase (JNK), respectively. NF-κB and JNK are important for mounting an immune response and causing tissue inflammation. Moreover, the current belief is that NF-κB protects hepatocytes from death, whereas JNK promotes apoptosis. Consequently, NF-κB and JNK act as regulators of injury, this website death, proliferation, and dysplastic transformation of hepatocytes,5, 6 making any molecule that activates these pathways, such as TAK1, a potential therapeutic target. A role for TAK1 in the liver was first reported in 2001 in two studies from the Brenner group describing how TAK1 activated JNK and maintained hepatocyte quiescence7 and controlled the proliferation of stellate cells.8 One year later,

Liedtke et al.9 elucidated TAK1′s role in hepatocyte apoptosis by showing increased apoptosis after inhibition of the TAK1/JNK pathway. Because of the lack of mice with inactivation of Map3k7, the gene encoding TAK1, these studies relied on selleckchem adenoviruses to express dominant-negative sequences in mice. Despite these intriguing findings, TAK1 was one of the least studied MAP3Ks in the last 上海皓元医药股份有限公司 decade. However, the generation of mice carrying floxed Map3k7 alleles restored interest in this regulator.10 For example, Tang et al. crossed these mice with mice transgenic

for Mx1-Cre, an interferon-inducible Cre recombinase. Upon injection of the interferon inducer polyinosinic:polycytidylic acid, Cre-mediated recombination resulted in TAK1 deficiency mainly in hematopoietic cells, but also in hepatocytes.11 Surprisingly, this caused cholestasis, massive hepatocyte apoptosis, and destruction of the normal liver architecture followed by death from liver failure 8-10 days after polyinosinic:polycytidylic acid injection. These results provided a starting point for two studies published this year that examined the function of TAK1 specifically in the liver. The first study by Inokuchi et al. appeared in Proceedings of the National Academy of Sciences of the U.S.A.3 and was quickly followed by the study from Bettermann et al. published in Cancer Cell.4 Both studies focused on the role of TAK1 in HCC development. Inokuchi et al. crossed mice carrying floxed Map3k7 alleles with mice expressing Cre from an albumin enhancer/promoter construct (Table 1).