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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; CELL ; Germany ; PATHWAY ; PROTEIN ; MOLECULES ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; nuclear bodies ; BINDING ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; SIGNAL ; MOLECULE ; PROGRESSION ; AMPLIFICATION ; TRANSCRIPTIONAL ACTIVITY ; CELL-DEATH ; COMPONENT ; LOCALIZATION ; NUCLEUS ; MITOCHONDRIA ; BODY ; GLUCOCORTICOID-RECEPTOR ; S-PHASE ; CASPASE 8 ; SIGNALING COMPLEX ; NUCLEAR-BODIES ; PML ; CD95 ; CASPASE-8 ACTIVATION ; signaling ; BODIES ; RE ; assembly ; CASPASE-8 ; regulation ; SIGNALING COMPLEXES ; NUCLEAR ; senescence ; USA ; function ; SIGNALS ; - ; FADD ; FLASH ; apoptosis regulation ; CASPASE-8/FLICE
    Abstract: The CD95 receptor signals via assembly of a multi-protein complex termed death-inducing signaling complex ( DISC) which triggers activation of receptor-bound caspase-8/FLICE molecules. Most cells ( type II cells) depend on a mitochondrial amplification pathway to commit apoptosis upon CD95 activation. The caspase-8-binding protein FLICE-associated huge protein ( FLASH) has been previously implicated in the regulation of caspase-8 activation at the DISC. However, recent findings demonstrated that FLASH is a Cajal body component and regulates progression through S-phase of the cell cycle in the nucleus. Our recent work identified FLASH as binding partner of the PML nuclear body ( PML NB) constituent Sp100 and demonstrated that FLASH partially localizes to PML NBs. Upon CD95 activation FLASH exits the nucleus and translocates to mitochondria where it meets caspase-8 to promote its activation. Our findings reconcile conflicting views on FLASH localization and its role in apoptosis regulation, and suggest that CD95 signals via a nuclear pathway. Potential implications of our findings for understanding FLASH function are discussed
    Type of Publication: Journal article published
    PubMed ID: 17377497
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  • 2
    Keywords: RECEPTOR ; APOPTOSIS ; CELL ; Germany ; INHIBITION ; PATHWAY ; DEATH ; PROTEIN ; RNA ; transcription ; ACTIVATION ; COMPLEX ; COMPLEXES ; FAMILY ; nuclear bodies ; COMPONENT ; MAMMALIAN-CELLS ; MITOCHONDRIA ; TRANSLOCATION ; GLUCOCORTICOID-RECEPTOR ; FLICE ; PML ; CD95 ; RE ; FAMILIES ; INTERFERENCE ; RNA INTERFERENCE ; CASPASE-8 ; MEDIATED APOPTOSIS ; senescence ; death receptor ; SIGNALS ; FLASH ; CD95 (Fas/APO-1)
    Abstract: Caspase-8-binding protein FLICE-associated huge protein ( FLASH) has been proposed to regulate death receptor CD95-induced apoptosis through facilitating caspase-8 activation at the death-inducing signaling complex. Here, we found that FLASH interacts with the PML nuclear body component Sp100 and predominantly resides in the nucleus and nuclear bodies (NBs). In response to CD95 activation, FLASH leaves the NBs and translocates into the cytoplasm where it accumulates at mitochondria. The nucleo-cytoplasmic translocation of FLASH requires CD95-induced caspase activation and is facilitated by the Crm1-dependent nuclear export pathway. Downregulation of FLASH by RNA interference or inhibition of its nucleocytoplasmic shuttling reduced CD95-induced apoptosis. Furthermore, we show that the adenoviral anti-apoptotic Bcl-2 family member E1B19K traps FLASH and procaspase-8 in a ternary complex at mitochondria, thereby blocking CD95-induced caspase-8 activation. Knock-down of Sp100 potentiated CD95-activated apoptosis through enhancing nucleo-cytoplasmic FLASH translocation. In summary, our findings suggest that CD95 signals via a previously unrecognized nuclear pathway mediated by nucleo-cytoplasmic translocation of FLASH
    Type of Publication: Journal article published
    PubMed ID: 17245429
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