Search: WFRF:(Frank R. A.)
> (2000-2004) >
Transient activatio...
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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
Publisher, publication year, extent ...
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2003-01-22
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Springer Science and Business Media LLC,2003
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-10478
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-10478URI
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https://doi.org/10.1038/sj.onc.1206132DOI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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
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Animals
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Apoptosis/drug effects/physiology
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Carcinoma; Hepatocellular/genetics/metabolism/pathology
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Cells; Cultured
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DNA-Binding Proteins/genetics/*metabolism
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Enzyme Activation
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Hepatocytes/cytology/metabolism
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I-kappa B Kinase
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I-kappa B Proteins/metabolism
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JNK Mitogen-Activated Protein Kinases
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Liver Neoplasms/genetics/metabolism/pathology
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MAP Kinase Kinase Kinases/genetics/*metabolism
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Mice
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Mice; Transgenic
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Mitogen-Activated Protein Kinases/metabolism
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NF-kappa B/genetics/*metabolism
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Phosphorylation
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Protein Transport/drug effects
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Protein-Serine-Threonine Kinases/genetics/*metabolism
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Proto-Oncogene Proteins c-myc/genetics/metabolism
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Signal Transduction
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Smad7 Protein
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Trans-Activators/genetics/*metabolism
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Transcription Factor AP-1/*metabolism
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Transforming Growth Factor beta/*metabolism/pharmacology
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Transforming Growth Factor beta1
Added entries (persons, corporate bodies, meetings, titles ...)
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Panta, Ganesh R.
(author)
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Bilyeu, Jennifer D.
(author)
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Cavin, Lakita G.
(author)
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Sovak, Mika A.
(author)
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Oliver, Aundrea A.
(author)
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Factor, Valentina
(author)
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Heuchel, RainerUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)rainheuc
(author)
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Mercurio, Frank
(author)
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Thorgeirsson, Snorri S.
(author)
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Sonenshein, Gail E.
(author)
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Uppsala universitetLudwiginstitutet för cancerforskning
(creator_code:org_t)
Related titles
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In:Oncogene: Springer Science and Business Media LLC22:3, s. 412-4250950-92321476-5594
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Oncogene
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Arsura, Marcello
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Panta, Ganesh R.
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Bilyeu, Jennifer ...
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Cavin, Lakita G.
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Sovak, Mika A.
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Oliver, Aundrea ...
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Factor, Valentin ...
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Heuchel, Rainer
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Mercurio, Frank
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Thorgeirsson, Sn ...
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Sonenshein, Gail ...
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Oncogene
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Uppsala University