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.

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MARC

Arsura, Marcello (author)

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.

Article/chapterEnglish2003

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2003-01-22
Springer Science and Business Media LLC,2003
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LIBRIS-ID:oai:DiVA.org:uu-10478
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-10478URI
https://doi.org/10.1038/sj.onc.1206132DOI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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.

Subject headings and genre

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

Added entries (persons, corporate bodies, meetings, titles ...)

Panta, Ganesh R. (author)
Bilyeu, Jennifer D. (author)
Cavin, Lakita G. (author)
Sovak, Mika A. (author)
Oliver, Aundrea A. (author)
Factor, Valentina (author)
Heuchel, RainerUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)rainheuc (author)
Mercurio, Frank (author)
Thorgeirsson, Snorri S. (author)
Sonenshein, Gail E. (author)
Uppsala universitetLudwiginstitutet för cancerforskning (creator_code:org_t)

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In:Oncogene: Springer Science and Business Media LLC22:3, s. 412-4250950-92321476-5594

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By the author/editor: Arsura, Marcello; Panta, Ganesh R.; Bilyeu, Jennifer ...; Cavin, Lakita G.; Sovak, Mika A.; Oliver, Aundrea ...; show more...; Factor, Valentin ...; Heuchel, Rainer; Mercurio, Frank; Thorgeirsson, Sn ...; Sonenshein, Gail ...; show less...

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