Gene interactions and pathways from curated databases and text-mining
Oncogene 2003, PMID: 12545162

Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation.

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

NF-kappaB has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-kappaB activity by TGF-beta1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-kappaB is transiently activated in response to TGF-beta1 treatment. Here we elucidate the mechanism of TGF-beta1-mediated regulation of NF-kappaB and induction of apoptosis in epithelial cells. We report that TGF-beta1 activates IKK kinase, which mediates IkappaB-alpha phosphorylation. In turn, the activation of IKK following TGF-beta1 treatment is mediated by the TAK1 kinase. As a result of NF-kappaB activation, IkappaB-alpha mRNA and protein levels are increased leading to postrepression of NF-kappaB and induction of cell death. Inhibition of NF-kappaB following TGF-beta1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-beta1-mediated upregulation of Smad7 appeared independent of NF-kappaB. In hepatocellular carcinomas of TGF-beta1 or TGF-alpha/c-myc transgenic mice, we observed constitutive activation of NF-kappaB that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-kappaB/IkappaB-alpha signaling to negatively regulate NF-kappaB levels thereby permitting TGF-beta1-induced apoptosis through AP-1 activity.

Diseases/Pathways annotated by Medline MESH: Carcinoma, Hepatocellular, Liver Neoplasms
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Text Mining Data

AP-1/SMAD ⊣ TGF-beta1: " Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis : implications in liver tumor formation "

AP-1/SMAD ⊣ NF-kappaB: " Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis : implications in liver tumor formation "

AP-1/SMAD ⊣ TGF-beta1: " Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis : implications in liver tumor formation "

AP-1/SMAD ⊣ NF-kappaB: " Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis : implications in liver tumor formation "

TGF-beta1 → NF-kappaB: " Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis : implications in liver tumor formation "

NF-kappaB → TGF-beta1: " Here we elucidate the mechanism of TGF-beta1 mediated regulation of NF-kappaB and induction of apoptosis in epithelial cells "

AP-1 complex ⊣ NF-kappaB: " Inhibition of NF-kappaB following TGF-beta1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs mediated cell killing "

c-Jun ⊣ NF-kappaB: " Inhibition of NF-kappaB following TGF-beta1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs mediated cell killing "

Smad7 → TGF-beta1: " Furthermore, TGF-beta1 mediated upregulation of Smad7 appeared independent of NF-kappaB "

Smad7 — NF-kappaB: " Furthermore, TGF-beta1 mediated upregulation of Smad7 appeared independent of NF-kappaB "

Manually curated Databases

No curated data.