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Transient activatio...
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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Arsura, Marcello (author)
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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, Rainer (author)
- Uppsala universitet,Ludwiginstitutet för cancerforskning
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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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(creator_code:org_t)
- 2003-01-22
- 2003
- English.
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In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 22:3, s. 412-425
- Related links:
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http://www.ncbi.nlm....
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https://www.nature.c...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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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.
Keyword
- 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
Publication and Content Type
- ref (subject category)
- art (subject category)
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Oncogene
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- By the author/editor
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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 ...
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Sonenshein, Gail ...
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show less...
- Articles in the publication
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Oncogene
- By the university
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Uppsala University