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.
2003 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 3, 412-425 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2003. Vol. 22, no 3, 412-425 p.
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
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-10478DOI: 10.1038/sj.onc.1206132PubMedID: 12545162OAI: oai:DiVA.org:uu-10478DiVA: diva2:38246