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  • DEATH  (3)
  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; CELL ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; PATHWAY ; PATHWAYS ; DEATH ; GENE ; GENE-EXPRESSION ; PROTEIN ; transcription ; cell line ; LINES ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; LIGAND ; COMPLEXES ; TRANSCRIPTION FACTOR ; INDUCTION ; CONTRAST ; KERATINOCYTES ; SKIN ; CELL-LINES ; treatment ; TARGET ; gene expression ; resistance ; CD95 ligand ; CELL-DEATH ; CELL-LINE ; LINE ; MODULATION ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; HUMAN KERATINOCYTES ; RECRUITMENT ; sensitivity ; RECEPTORS ; cell lines ; TRAIL ; DISC ; SIGNALING COMPLEX ; inflammation ; HaCaT ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CASPASE-8 ACTIVATION ; signaling ; keratinocyte ; TARGET GENE ; BIOCHEMICAL-CHARACTERIZATION ; C-FLIP ; DOMAIN KINASE RIP ; GENE INDUCTION ; SIGNALING COMPLEXES ; TNF RECEPTOR
    Abstract: Human keratinocytes undergo apoptosis following treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via surface-expressed TRAIL receptors 1 and 2. In addition, TRAIL triggers nonapoptotic signaling pathways including activation of the transcription factor NF-kappaB, in particular when TRAIL-induced apoptosis is blocked. The intracellular protein cFLIP(L) interferes with TRAIL-induced apoptosis at the death-inducing signaling complex (DISC) in many cell types. To study the role of cFLIP(L) in TRAIL signaling, we established stable HaCaT keratinocyte cell lines expressing varying levels of cFLIP(L). Functional analysis revealed that relative cFLIP(L) levels correlated with apoptosis resistance to TRAIL. Surprisingly, cFLIP(L) specifically blocked TRAIL-induced NF-kappaB activation and TRAIL-dependent induction of the proinflammatory target gene interleukin-8. Biochemical characterization of the signaling pathways involved showed that apoptosis signaling was inhibited at the DISC in cFLIP(L)-overexpressing keratinocytes, although cFLIP(L) did not significantly impair enzymatic activity of the receptor complex. In contrast, recruitment and modification of receptor-interacting protein was blocked in cFLIP(L)-overexpressing cells. Taken together, our data demonstrate that cFLIP(L) is not only a central antiapoptotic modulator of TRAIL-mediated apoptosis but also an inhibitor of TRAIL-induced NF-kappaB activation and subsequent proinflammatory target gene expression. Hence, cFLIP(L) modulation in keratinocytes may not only influence apoptosis sensitivity but may also lead to altered death receptor-dependent skin inflammation
    Type of Publication: Journal article published
    PubMed ID: 15459191
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  • 2
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; tumor ; CELL ; COMBINATION ; Germany ; human ; PATHWAY ; PATHWAYS ; DEATH ; PROTEIN ; PROTEINS ; NF-KAPPA-B ; TUMOR-NECROSIS-FACTOR ; LIGAND ; BIOLOGY ; CELL-LINES ; DOWN-REGULATION ; MOLECULAR-BIOLOGY ; SUPPRESSION ; SIGNAL ; TARGET ; resistance ; CELL-DEATH ; UP-REGULATION ; genetics ; CELL-LINE ; MODULATION ; MELANOMA ; METASTATIC MELANOMA ; SIGNALING PATHWAY ; ONCOGENE ; LIGANDS ; HUMAN KERATINOCYTES ; sensitivity ; heredity ; TRAIL ; DEATH RECEPTORS ; SIGNALING COMPLEX ; APOPTOSIS-INDUCING LIGAND ; signaling ; molecular biology ; molecular ; ONCOLOGY ; MELANOMA-CELLS ; C-FLIP ; death receptor ; LOSSES ; ENGLAND ; PREDICT ; BCL-2 FAMILY ; CELL BIOLOGY ; cFLIP ; RECEPTOR-SELECTIVE MUTANTS ; TRAIL-R1 ; TRAIL-R2
    Abstract: Death ligands such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and certain forms of CD95L are attractive therapeutic options for metastatic melanoma. Since knowledge about the regulation of death receptor sensitivity in melanoma is sparse, we have analysed these signaling pathways in detail. The loss of CD95 or TRAIL-R1, but not of TRAIL-R2, surface expression correlated with apoptosis sensitivity in a panel of melanoma cell lines. In contrast, the expression of proteins of the apical apoptosis signaling cascade (FADD, initiator caspases-8 and cFLIP) did not predict apoptosis sensitivity. Since both TRAIL-R1 and -R2 transmit apoptotic signals, we asked whether cFLIP, highly expressed in several of the cell lines tested, is sufficient to maintain resistance to TRAIL-R2-mediated apoptosis. Downregulation of cFLIP in TRAIL-R2-positive, TRAIL-resistant IGR cells dramatically increased TRAIL sensitivity. Conversely ectopic expression of cFLIP in TRAIL-sensitive, TRAIL-R2-expressing RPM-EP melanoma cells inhibited TRAIL- and CD95L- mediated cell death. Thus, modulation of cFLIP is sufficient to sensitize TRAIL-R2-expressing cells for TRAIL. Taken together, albeit expressing all proteins necessary for death receptor-mediated apoptosis, TRAIL-R1 negative melanoma cells cannot undergo TRAIL- or CD95L-induced apoptosis due to expression of cFLIP. Hence, cFLIP represents an attractive therapeutic target for melanoma treatment, especially in combination with TRAIL receptor agonists
    Type of Publication: Journal article published
    PubMed ID: 18084329
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  • 3
    Keywords: TRAIL ; MELANOMA ; CELLS ; RECEPTOR ; APOPTOSIS ; CELL ; human ; DEATH ; death receptor
    Type of Publication: Meeting abstract published
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