Transforming growth factor β can mediate apoptosis via the expression of TRAIL in human hepatoma cells

Herzer, Kerstin; Ganten, Tom M.; Schulze‐Bergkamen, Henning; Grosse‐Wilde, Anne; Koschny, Ronald; Krammer, Peter H.; Walczak, Henning

doi:10.1002/hep.20757

Cited by 29 publications

(27 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results clearly show a significant decrease of apoptosis of CEM cells upon coincubation with those hepatoma cells that were pretreated with siRNA for Smad4, JunD, or FosB before TGF-h stimulation, compared with Huh7 cells that were pretreated with control siRNA. Compromised TRAIL expression by silencing these signal transduction components correlates clearly to our previously published results, using TRAIL-R2-Fc to efficiently and specifically inhibit TGF-h -induced apoptosis in hepatoma cells (11). Therefore, TGF-h -induced TRAIL expression and function is dependent on functional expression of Smad4 as well as of the AP-1 components JunD and FosB.…”

Section: Silencing Of Ap-1 Components and Smad4 Severely Impairs Tgf-supporting

confidence: 88%

“…We previously examined a potential role of various death receptor/ligand systems in TGF-h -induced apoptosis and have identified the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as an important mediator of TGF-h -induced apoptosis in hepatoma cells (11). TRAIL belongs to a family of death ligand systems and has attracted attention for its ability to preferentially kill a wide variety of tumor cell lines (12,13), whereas most normal cells are resistant to TRAIL both in vitro and in vivo (14,15).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Herzer

Grosse‐Wilde

Krammer

et al. 2008

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

Transforming growth factor-B (TGF-B) 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-B -induced apoptosis in hepatoma cells. In this study, we have further explored the mechanism by which TGF-B 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 À1950 to À1100 responsible for TRAIL induction following treatment with TGF-B. Within this region, we have identified an activator protein-1 (AP-1) site indispensable for TGF-B -mediated induction of TRAIL. Activation of this AP-1 site is mediated by a JunDÁFosB heterodimer. Expression of DNSmad4, DNJunD, or DNFosB significantly impairs TGF-B -mediated activation of the TRAIL promoter. Furthermore, with tRNA interference targeting Smad4, junD, FosB, we could abolish TRAIL expression and, subsequently, TGF-B -induced TRAIL-mediated apoptosis in hepatoma cells. Our results reveal a new AP-1 site within the TRAIL promoter functionally involved in TGF-B -induced TRAIL expression and apoptosis in hepatomas and thus provide evidence for the underlying mechanism by which TGF-B might regulate cell death in liver cancer.

show abstract

Section: Silencing Of Ap-1 Components and Smad4 Severely Impairs Tgf-supporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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

Herzer

Grosse‐Wilde

Krammer

et al. 2008

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although our data argue against a role for TRAIL in TGFh1-mediated NRP apoptosis, it remains possible that the human TRAIL receptorFc fusions we employed failed to block rat TRAIL signaling because of sequence differences between the human and rat TRAIL receptors. Consistent with this possibility, others have reported that human DR4-Fc inhibits TGFh1-induced apoptosis of human hepatoma cell lines (50).…”

Section: Discussionsupporting

confidence: 54%

FLICE-Like Inhibitory Protein Blocks Transforming Growth Factor β1–Induced Caspase Activation and Apoptosis in Prostate Epithelial Cells

Nastiuk

Yoo

et al. 2008

Molecular Cancer Research

View full text Add to dashboard Cite

Androgen withdrawal induces the regression of human prostate cancers, but such cancers eventually become androgen-independent and metastasize. Thus, deciphering the mechanism of androgen withdrawalinduced apoptosis is critical to designing new therapies for prostate cancer. Previously, we showed that in the rat, castration-induced apoptosis is accompanied by a reduction in the expression of the apical caspase inhibitor FLICE-like inhibitory protein (FLIP). To test the functional role of FLIP in inhibiting prostate epithelial cell apoptosis, we employed the rat prostate epithelial cell line NRP-152, which differentiates to a secretory phenotype in a low-mitogen medium and then undergoes apoptosis following the addition of transforming growth factor B1 (TGFB1), mimicking androgen withdrawal -induced apoptosis. FLIP levels decline with TGFB1 treatment, suggesting that apoptosis is mediated by caspase-8 and indeed the caspase inhibitor crmA blocks TGFB1-induced apoptosis. Small interfering RNA -mediated knockdown of FLIP recapitulates and enhances TGFB1-induced cell death. NRP-152 cells stably transfected with constitutively expressed FLIP were refractory to TGFB1-induced apoptosis. TGFB1-induced caspase-3 activity is proportional to the level of cell death and inversely proportional to the level of FLIP expression in various clones. Moreover, neither caspase-3 nor PARP is cleaved in clones expressing high levels of FLIP. Furthermore, insulin, which inhibits differentiation, increases FLIP and inhibits TGFB-induced death in a FLIP-dependent manner. Although neither Fas-Fc, sTNFRII-Fc, nor DR5-Fc blocked TGFB1-induced cell death, there is a significant increase in tumor necrosis factor mRNA following TGFB stimulation, suggesting both an unexpected role for tumor necrosis factor in this model system and the possibility that FLIP blocks another unknown caspase-dependent mediator of apoptosis. (Mol Cancer Res 2008;6(2):231 -42)

show abstract

“…TGFβ1 has demonstrated both growth-stimulatory and growth-suppressive functions depending on cellular context. [53][54][55] In contrast, we observed an approximately two-fold decrease in vascular endothelial growth factor (VEGF) RNA (Fig. 5C).…”

Section: Mammalian Cells With Reduced E1 Levels Show Altered Expressimentioning

confidence: 81%

Mutation of the Gene Encoding the Ubiquitin Activating Enzyme Uba1 Causes Tissue Overgrowth in Drosophila

Pfleger¹,

Harvey²,

Yan³

et al. 2007

Fly

View full text Add to dashboard Cite

Protein ubiquitination has been shown to regulate a wide variety of cellular process including cell cycle progression, protein trafficking and apoptosis. Most regulation of ubiquitination occurs at the level of E2 or E3 enzymes and their interactions with specific substrates. In a screen for mutations that cause tissue overgrowth, we recovered multiple mutations in the Drosophila Uba1 gene that encodes the E1 enzyme that is required for the first step of most, if not all, ubiquitination reactions. Previous studies with yeast and mammalian cells have shown that disrupting E1 function results in a cell-cycle arrest. Here we show that in the developing Drosophila eye, clones of cells that are homozygous for partial loss of function alleles of Uba1 show defects in apoptosis. Moreover, clones homozygous for stronger or complete loss of function alleles of Uba1, that are predicted to have a global defect on ubiquitination, survive poorly but are able to stimulate the overgrowth of adjacent wild-type tissue. Experiments with mammalian cells show that reducing the level of RNA of the mammalian Uba1 ortholog, UBE1, also results in increased expression of specific growth factor genes. Our studies show that a reduction in E1 activity can promote tissue growth in a multicellular organism and raise the possibility that changes in E1 activity may occur during normal development or in cancer.

show abstract

Transforming growth factor β can mediate apoptosis via the expression of TRAIL in human hepatoma cells

Cited by 29 publications

References 48 publications

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

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

FLICE-Like Inhibitory Protein Blocks Transforming Growth Factor β1–Induced Caspase Activation and Apoptosis in Prostate Epithelial Cells

Mutation of the Gene Encoding the Ubiquitin Activating Enzyme Uba1 Causes Tissue Overgrowth in Drosophila

Contact Info

Product

Resources

About