Transient activation of NF-|[kappa]|B through a TAK1|[sol]|IKK kinase pathway by TGF-|[beta]|1 inhibits AP-1|[sol]|SMAD signaling and apoptosis: implications in liver tumor formation

摘要

NF-B has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-B activity by TGF-1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-B is transiently activated in response to TGF-1 treatment. Here we elucidate the mechanism of TGF-1-mediated regulation of NF-B and induction of apoptosis in epithelial cells. We report that TGF-1 activates IKK kinase, which mediates IB- phosphorylation. In turn, the activation of IKK following TGF-1 treatment is mediated by the TAK1 kinase. As a result of NF-B activation, IB- mRNA and protein levels are increased leading to postrepression of NF-B and induction of cell death. Inhibition of NF-B following TGF-1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-1-mediated upregulation of Smad7 appeared independent of NF-B. In hepatocellular carcinomas of TGF-1 or TGF-/c-myc transgenic mice, we observed constitutive activation of NF-B that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-B/IB- signaling to negatively regulate NF-B levels thereby permitting TGF-1-induced apoptosis through AP-1 activity.