Transforming growth factor-β-mediated tumor necrosis factor-related apoptosis-inducing ligand expression and apoptosis in hepatoma cells requires functional cooperation between smad proteins and activator protein-1

Kerstin Herzer, Anne Grosse-Wilde, Peter H. Krammer, Peter R. Galle, Stephan Kanzler

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Abstract

Transforming growth factor-β (TGF-β) has been shown to induce apoptotic cell death in normal and transformed hepatocytes. We recently identified tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as an important mediator of TGF-β-induced apoptosis in hepatoma cells. In this study, we have further explored the mechanism by which TGF-β up-regulates TRAIL expression. The 5′-flanking region of the TRAIL gene was isolated and characterized. Deletion mutants of the 5′-untranslated region of the TRAIL gene revealed a region comprising nucleotides -1950 to -1100 responsible for TRAIL induction following treatment with TGF-β. Within this region, we have identified an activator protein-1 (AP-1) site indispensable for TGF-β-mediated induction of TRAIL. Activation of this AP-1 site is mediated by a JunD·FosB heterodimer. Expression of DNSmad4, DNJunD, or DNFosB significantly impairs TGF-β-mediated activation of the TRAIL promoter. Furthermore, with tRNA interference targeting Smad4, junD, FosB, we could abolish TRAIL expression and, subsequently, TGF-β-induced TRAIL-mediated apoptosis in hepatoma cells. Our results reveal a new AP-1 site within the TRAIL promoter functionally involved in TGF-β-induced TRAIL expression and apoptosis in hepatomas and thus provide evidence for the underlying mechanism by which TGF-β might regulate cell death in liver cancer.

Original languageEnglish (US)
Pages (from-to)1169-1177
Number of pages9
JournalMolecular Cancer Research
Volume6
Issue number7
DOIs
StatePublished - Jul 1 2008

Fingerprint

Smad Proteins
Transcription Factor AP-1
Transforming Growth Factors
Hepatocellular Carcinoma
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Cell Death
5' Flanking Region
5' Untranslated Regions
Liver Neoplasms
Transfer RNA
Genes
Hepatocytes
Up-Regulation
Nucleotides

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

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title = "Transforming growth factor-β-mediated tumor necrosis factor-related apoptosis-inducing ligand expression and apoptosis in hepatoma cells requires functional cooperation between smad proteins and activator protein-1",
abstract = "Transforming growth factor-β (TGF-β) has been shown to induce apoptotic cell death in normal and transformed hepatocytes. We recently identified tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as an important mediator of TGF-β-induced apoptosis in hepatoma cells. In this study, we have further explored the mechanism by which TGF-β up-regulates TRAIL expression. The 5′-flanking region of the TRAIL gene was isolated and characterized. Deletion mutants of the 5′-untranslated region of the TRAIL gene revealed a region comprising nucleotides -1950 to -1100 responsible for TRAIL induction following treatment with TGF-β. Within this region, we have identified an activator protein-1 (AP-1) site indispensable for TGF-β-mediated induction of TRAIL. Activation of this AP-1 site is mediated by a JunD·FosB heterodimer. Expression of DNSmad4, DNJunD, or DNFosB significantly impairs TGF-β-mediated activation of the TRAIL promoter. Furthermore, with tRNA interference targeting Smad4, junD, FosB, we could abolish TRAIL expression and, subsequently, TGF-β-induced TRAIL-mediated apoptosis in hepatoma cells. Our results reveal a new AP-1 site within the TRAIL promoter functionally involved in TGF-β-induced TRAIL expression and apoptosis in hepatomas and thus provide evidence for the underlying mechanism by which TGF-β might regulate cell death in liver cancer.",
author = "Kerstin Herzer and Anne Grosse-Wilde and Krammer, {Peter H.} and Galle, {Peter R.} and Stephan Kanzler",
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T1 - Transforming growth factor-β-mediated tumor necrosis factor-related apoptosis-inducing ligand expression and apoptosis in hepatoma cells requires functional cooperation between smad proteins and activator protein-1

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AU - Grosse-Wilde, Anne

AU - Krammer, Peter H.

AU - Galle, Peter R.

AU - Kanzler, Stephan

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