Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation

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Abstract
NF-κB has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-κB activity by TGF-β1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-κB is transiently activated in response to TGF-β1 treatment. Here we elucidate the mechanism of TGF-β1-mediated regulation of NF-κB and induction of apoptosis in epithelial cells. We report that TGF-β1 activates IKK kinase, which mediates IκB-α phosphorylation. In turn, the activation of IKK following TGF-β1 treatment is mediated by the TAK1 kinase. As a result of NF-κB activation, IκB-α mRNA and protein levels are increased leading to postrepression of NF-κB and induction of cell death. Inhibition of NF-κB following TGF-β1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-β1-mediated upregulation of Smad7 appeared independent of NF-κB. In hepatocellular carcinomas of TGF-β1 or TGF-α/c-myc transgenic mice, we observed constitutive activation of NF-κB that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-κB/IκB-α signaling to negatively regulate NF-κB levels thereby permitting TGF-β1-induced apoptosis through AP-1 activity.