| Autor: |
Arsura, Marcello, Panta, Ganesh R, Bilyeu, Jennifer D, Cavin, Lakita G, Sovak, Mika A, Oliver, Aundrea A, Factor, Valentina, Heuchel, Rainer, Mercurio, Frank, Thorgeirsson, Snorri S, Sonenshein, Gail E |
| Předmět: |
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| Zdroj: |
Oncogene; 1/23/2003, Vol. 22 Issue 3, p412, 14p |
| Abstrakt: |
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.Oncogene (2003) 22, 412–425. doi:10.1038/sj.onc.1206132 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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