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 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.

Nyckelord

Animals

Apoptosis/drug effects/physiology

Carcinoma; Hepatocellular/genetics/metabolism/pathology

Cells; Cultured

DNA-Binding Proteins/genetics/*metabolism

Enzyme Activation

Hepatocytes/cytology/metabolism

I-kappa B Kinase

I-kappa B Proteins/metabolism

JNK Mitogen-Activated Protein Kinases

Liver Neoplasms/genetics/metabolism/pathology

MAP Kinase Kinase Kinases/genetics/*metabolism

Mice

Mice; Transgenic

Mitogen-Activated Protein Kinases/metabolism

NF-kappa B/genetics/*metabolism

Phosphorylation

Protein Transport/drug effects

Protein-Serine-Threonine Kinases/genetics/*metabolism

Proto-Oncogene Proteins c-myc/genetics/metabolism

Signal Transduction

Smad7 Protein

Trans-Activators/genetics/*metabolism

Transcription Factor AP-1/*metabolism

Transforming Growth Factor beta/*metabolism/pharmacology

Transforming Growth Factor beta1

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)