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  • PATHWAY  (32)
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  • 1
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; PATHWAY ; PATHWAYS ; VITRO ; SYSTEM ; DEATH ; DISTINCT ; TIME ; COMPLEX ; COMPLEXES ; primary ; T cell ; T cells ; T-CELL ; T-CELLS ; culture ; activation-induced cell death ; CELL-DEATH ; UP-REGULATION ; CYCLE PROGRESSION ; DISPLAY ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; B-CELLS ; immune response ; IMMUNE-RESPONSE ; IL-2 ; INITIATION ; FAS-MEDIATED APOPTOSIS ; DISC ; SIGNALING COMPLEX ; ANTIGEN RECEPTOR ; C-FLIPSHORT ; CD95 ; COMPLEX DISC ; FLICE-INHIBITORY PROTEIN ; INTERLEUKIN-2 RECEPTOR
    Abstract: The CD95 (APO-1/Fas) system plays a critical role in activation-induced cell death (AICD) of T cells. We previously described two distinct CD95 (APO-1/Fas) signaling pathways: 1) type I cells show strong death-inducing signaling complex (DISC) formation and mitochondria-independent apoptosis and 2) DISC formation is reduced in type II cells, leading to mitochondria-dependent apoptosis. To investigate the relevance of these pathways, we set up an in vitro model that mimics the initiation and the down phase of an immune response, respectively. Freshly activated human T cells (initiation) are resistant toward CD95-mediated AICD despite high expression of CD95. We previously reported that these T cells show reduced DISC formation. In this study, we show that freshly activated T cells are CD95-type II cells that show high expression levels of Bcl-x(L) and display a block in the mitochondrial apoptosis pathway. Furthermore, we show that, upon prolonged culture (down phase), human T cells undergo a switch from type II to type I cells that renders T cells sensitive to CD95-mediated AICD. Finally, we demonstrate that this switch is dependent on the presence of IL-2. Our observations reveal for the first time that the existence of coexisting CD95 signaling pathways is of physiological relevance
    Type of Publication: Journal article published
    PubMed ID: 12960316
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  • 2
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; VITRO ; DEATH ; GENE ; PROTEIN ; RNA ; LINES ; gene transfer ; GENE-TRANSFER ; MECHANISM ; RAT ; CONTRAST ; mechanisms ; CELL-LINES ; PROTEIN-KINASE ; CLEAVAGE ; resistance ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; MEMBRANE ; LINE ; KAPPA-B ; sensitivity ; OVEREXPRESSION ; cell lines ; CASPASE-8 CLEAVAGE ; SIGNALING COMPLEX ; CASPASE ; INHIBITORS ; RE ; GLIOMA ; CASPASE-8 ; OLIGONUCLEOTIDE ; NEURONS ; C-FLIP ; cell death ; ANTISENSE OLIGONUCLEOTIDE ; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME ; CEREBELLAR GRANULE NEURONS ; Fas/CD95 ; IMMUNE PRIVILEGE ; lifeguard ; PHOSPHATIDYLINOSITOL 3-KINASE ; PI3-kinase/ Akt
    Abstract: The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI3-kinase, overexpression of the inhibitory protein I kappa B, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e. g., inhibition of the PI3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL
    Type of Publication: Journal article published
    PubMed ID: 16033886
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; Germany ; KINASE ; PATHWAY ; DEATH ; PROTEIN ; PROTEINS ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; DENDRITIC CELLS ; T-CELLS ; BINDING ; CLEAVAGE ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; B-CELLS ; SIGNALING COMPLEX ; signaling ; MALIGNANT-CELLS ; RE ; FAS ; CASPASE ACTIVATION ; C-FLIP ; IKK ; death receptor ; FLICE-INHIBITORY PROTEINS ; LONG FORM ; RECEPTOR-INDUCED APOPTOSIS
    Abstract: c-FLIP proteins (isoforms: c-FLIPL, c-FLIPS, and c-FLIPR) play an essential role in the regulation of death receptor - induced apoptosis. Here, we demonstrate that the cytoplasmic NH2-terminal procaspase-8 cleavage product of c-FLIP (p22-FLIP) found in nonapoptotic malignant cells, primary T and B cells, and mature dendritic cells (DCs) strongly induces nuclear factor kappa B (NF-kappa B) activity by interacting with the I kappa B kinase (IKK) complex via the IKK gamma subunit. Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-kappa B activation and life/death decisions in lymphocytes and DCs
    Type of Publication: Journal article published
    PubMed ID: 16682493
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; INHIBITION ; PATHWAY ; PATHWAYS ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEINS ; RNA ; DRUG ; MONOCLONAL-ANTIBODY ; TUMORS ; RELEASE ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; LIGAND ; MECHANISM ; FAMILY ; DOMAIN ; INDUCTION ; mechanisms ; DOWN-REGULATION ; CYTOCHROME-C ; MITOCHONDRIA ; UNITED-STATES ; RECEPTORS ; OVEREXPRESSION ; TUMOR CELLS ; Bcl-2 ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CD95 ; CASPASE ; INHIBITORS ; signaling ; FAMILIES ; SOLID TUMORS ; CYCLOOXYGENASE-2 ; TUMOR-CELL ; death receptor ; downregulation ; function ; caspases ; DRUGS ; cyclooxygenase ; RELEVANCE ; NECROSIS ; MCL-1 ; CELECOXIB-INDUCED APOPTOSIS ; PRIMARY HUMAN HEPATOCYTES
    Abstract: Inhibition of cyclooxygenase (COX)-2 elicits chemopreventive and therapeutic effects in solid tumors that are coupled with the induction of apoptosis in tumor cells. We investigated the mechanisms by which COX-2 inhibition induces apoptosis in hepatocellular carcinoma (HCC) cells. COX-2 inhibition triggered expression of the CD95, tumor necrosis factor (TNIF)-R, and TNF-related apoptosis-inducing ligand (TRAIL)-R1 and TRAIL-R2 death receptors. Addition of the respective specific ligands further increased apoptosis, indicating that COX-2 inhibition induced the expression of functional death receptors. Overexpression of a dominant-negative Fas-associated death domain mutant reduced COX-2 inhibitor-mediated apoptosis. Furthermore, our findings showed a link between COX-2 inhibition and the mitochondrial apoptosis pathway. COX-2 inhibition led to a rapid down-regulation of myeloid cc leukemia-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, followed by translocation of Bax to mitochondria and cytochrome c release front mitochondria. Consequently, overexpression of Mcl-1 led to inhibition of COX-2 inhibitor-mediated apoptosis. Furthermore, blocking endogenous Mcl-1 function using a small - interfering RNA approach enhanced COX-2 inhibitor-mediated apoptosis. It is of clinical importance that celecoxib acted synergistically with chemotherapeutic drugs in the induction of apoptosis in HCC cells. The clinical relevance of these results is further substantiated by the finding that COX-2 inhibitors did not sensitize primary human hepatocytes toward chemotherapy-induced apoptosis. In conclusion, COX-2 inhibition engages different apoptosis pathways in HCC cells stimulating death receptor signaling, activation of caspases, and apoptosis originating from mitochondria
    Type of Publication: Journal article published
    PubMed ID: 16849551
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; Germany ; human ; PATHWAY ; PATHWAYS ; LINES ; ACTIVATION ; COMPLEX ; LIGAND ; COMPLEXES ; MECHANISM ; INDUCTION ; CELL-LINES ; CELL-DEATH ; NUMBER ; CELL-LINE ; LINE ; CANCER-CELLS ; CYTOCHROME-C ; cell lines ; DISC ; SIGNALING COMPLEX ; CD95 ; signaling ; PROGRAM ; RE ; FAS ; MEDIATED APOPTOSIS ; SIGNALING COMPLEXES ; ADAPTER MOLECULE
    Abstract: Caspase-2 was reported to be involved in a number of apoptotic pathways triggered by various stimuli. However, the molecular mechanism of procaspase-2 activation in the course of apoptosis remains poorly defined. In this report, we demonstrate that procaspase-2 is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex (DISC) in human T- and B-cell lines. We show that procaspase-2 is activated at the DISC on CD95 stimulation. Despite its presence at the DISC, caspase-2 does not initiate apoptosis on CD95 stimulation in caspase-8-deficient cell lines. Taken together, our data reveal that caspase-2 is activated at the DISC but does not play an initiating role in the CD95-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 16822901
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; IN-VITRO ; tumor ; CELL ; IN-VIVO ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; VITRO ; VIVO ; SYSTEM ; SYSTEMS ; DEATH ; GENE ; GENES ; microarray ; PROTEIN ; transcription ; EPITHELIA ; TUMORS ; validation ; MICE ; TRANSCRIPTION FACTOR ; KERATINOCYTES ; SKIN ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; TARGET ; ISOFORM ; ENCODES ; PROMOTER ; PROMOTERS ; REQUIRES ; DNA-DAMAGE ; BAX ; HUMAN KERATINOCYTES ; SQUAMOUS-CELL CARCINOMA ; TARGETS ; RECEPTORS ; MICROARRAY ANALYSIS ; epidermis ; TRAIL ; DEATH RECEPTORS ; tetramer ; CD95 ; chemoresistance ; review ; TUMOR-SUPPRESSOR ; keratinocyte ; LIGHT ; TUMORIGENESIS ; development ; STRATIFIED EPITHELIA ; TARGET GENES ; analysis ; P63 ; death receptor ; EPITHELIUM ; EPITHELIAL TUMORS ; KINASE C-ABL ; P53-DEPENDENT APOPTOSIS ; REGULATES P73 ; USA ; function ; in vivo ; E ; PROTECTS ; MAINTENANCE ; inactive ; cornification ; FAMILY-MEMBER GENES ; GENE ENCODES ; IKK alpha ; ISOFORM EXPRESSION ; P53 HOMOLOG P63
    Abstract: The epidermis is a multilayered stratified epithelium, continuously regenerated by differentiating keratinocytes, that requires the transcription factor p63 for its development and maintenance. The TP63 gene encodes two major protein isoforms, TAp63 and Delta Np63, which have both transactivating and transcriptional repressing activities and regulate a wide range of target genes. TAp63 shows clear pro-apoptotic activity, mediated both by death receptors (CD95, TNF, TRAIL) and mitochondrial (bax, puma) pathways. Conversely, DNp63 protects from apoptosis by directly competing for TAp63 target promoters or sequestering it, forming inactive tetramers. Accordingly, p63 is expressed in epithelial tumors, contributing to both tumorigenesis and chemoresistance. However, the predominant physiological role of p63 is in epithelial development, as demonstrated by the lack of epidermis and other epithelia in p63-deficient mice. The specific role of TAp63 and DNp63 isoforms in epithelial development remains mostly unclear. Nevertheless, recent work utilizing in vivo genetic complementation of TAp63 and/or DNp63 into a p63 null background has shed new light into the specific functions of the two isoforms and allowed the in vivo validation of several p63 transcriptional targets, originally identified by microarray analysis in in vitro systems. However, despite concerted efforts to address the role of p63 isoforms, several questions remain unanswered. The main aim of this review is to critically discuss the data available in the literature and thoroughly analyze the models proposed
    Type of Publication: Journal article published
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  • 7
    Keywords: APOPTOSIS ; CELLS ; BLOOD ; CELL ; Germany ; IN-VIVO ; KINASE ; PATHWAY ; PATHWAYS ; SYSTEM ; DEATH ; PROTEIN ; PROTEINS ; RNA ; MICE ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; FAMILY ; primary ; INDUCTION ; T cell ; T cells ; T-CELL ; T-CELLS ; MEMBER ; MEMBERS ; TRANSGENIC MICE ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; B-CELLS ; SIGNALING COMPLEX ; Bcl-2 ; molecular ; MOLECULAR-BASIS ; RE ; FAMILIES ; LIFE ; LEVEL ; cell death ; ANTIGEN RECEPTORS ; progenitor ; SUPPRESSOR ; FAS LIGAND ; AICD ; HEMATOPOIETIC PROGENITOR KINASE-1 ; USA ; B-LYMPHOCYTES ; FATE ; FRAGMENT ; FAMILY-MEMBER BIM ; B-CELL ; KINASE-1 ; EXPANSION ; caspase-3 ; block ; B cells ; BCL-2 FAMILY ; COMPLEMENT ; FULL-LENGTH ; MEDIATED CLEAVAGE ; SMALL INTERFERING RNA
    Abstract: Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-KB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-KB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappa B-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim.Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 17712048
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; CELL ; Germany ; MODEL ; PATHWAY ; DEATH ; MONOCLONAL-ANTIBODY ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; DOMAIN ; INDUCTION ; T-CELLS ; BIOLOGY ; MOLECULAR-BIOLOGY ; SEQUENCE ; STIMULATION ; CLEAVAGE ; SUBUNIT ; CELL-DEATH ; INDUCED APOPTOSIS ; DOMAINS ; SIGNALING COMPLEX DISC ; SIGNALING COMPLEX ; CASPASE-8 ACTIVATION ; signaling ; molecular biology ; CASPASE-8 ; FAS ; EVENTS ; USA ; caspases ; OCCURS ; death-receptor
    Abstract: Caspase-8 is the main initiator caspase in death receptor-induced apoptosis. Procaspase-8 is activated at the death-inducing signaling complex (DISC). Previous studies suggested a two-step model of procaspase-8 activation. The first cleavage step occurs between the protease domains p18 and p10. The second cleavage step takes place between the prodomain and the large protease subunit (p18). Subsequently, the active caspase-8 heterotetramer p18(2)-p10(2) is released into the cytosol, starting the apoptotic signaling cascade. In this report, we have further analyzed procaspase-8 processing upon death receptor stimulation directly at the DISC and in the cytosol. We have found an alternative sequence of cleavage events for procaspase-8. We have demonstrated that the first cleavage can also occur between the prodomain and the large protease subunit (p18). The resulting cleavage product, p30, contains both the large protease subunit (p18) and the small protease subunit (p10). p30 is further processed to p10 and p18 by active caspases. Furthermore, we show that p30 can sensitize cells toward death receptor-induced apoptosis. Taken together, our data suggest an alternative mechanism of procaspase-8 activation at the DISC
    Type of Publication: Journal article published
    PubMed ID: 19528225
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  • 9
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; IN-VIVO ; PATHWAY ; VIVO ; DEATH ; DISEASE ; HEPATOCELLULAR-CARCINOMA ; liver ; PROTEIN ; TUMORS ; MICE ; MECHANISM ; FAMILY ; MARKER ; CARCINOGENESIS ; DELETION ; hepatocellular carcinoma ; CELL-DEATH ; AGE ; DAMAGE ; REGULATOR ; MITOSIS ; Bcl-2 ; INJURY ; HUMAN CANCER ; SURVIVIN ; cell death ; CANCERS ; HOMEOSTASIS ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; LIVER-REGENERATION
    Abstract: Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1(Delta hep)), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in 〉50% of Mcl-1(Delta hep) mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1(flox/wt) mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1(Delta hep) mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases. (HEPATOLOGY 2010;51:1226-1236.)
    Type of Publication: Journal article published
    PubMed ID: 20099303
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  • 10
    Keywords: APOPTOSIS ; CANCER ; Germany ; MODEL ; PATHWAY ; PATHWAYS ; INFORMATION ; NETWORK ; NETWORKS ; SYSTEM ; SYSTEMS ; DEATH ; DISEASE ; DISEASES ; NEW-YORK ; TRANSDUCTION ; COMPLEX ; COMPLEXES ; MECHANISM ; QUALITY ; mechanisms ; signal transduction ; SIGNAL ; IDENTIFICATION ; SIGNAL-TRANSDUCTION ; SIGNALING PATHWAYS ; PARAMETERS ; sensitivity ; parameter estimation ; REVEALS ; ROBUSTNESS ; RECEPTORS ; BEHAVIOR ; DISC ; FLICE-INHIBITORY PROTEIN ; AUTOIMMUNITY ; COMPLEXITY ; BIOCHEMICAL PATHWAYS ; CD95-induced apoptosis ; FRAMEWORK ; mathematical modeling ; MOLECULAR-MECHANISM ; sensitivity analysis ; threshold mechanism
    Abstract: Mathematical modeling is required for understanding the complex behavior of large signal transduction networks. Previous attempts to model signal transduction pathways were often limited to small systems or based on qualitative data only. Here, we developed a mathematical modeling framework for understanding the complex signaling behavior of CD95(APO-1/Fas)-mediated apoptosis. Defects in the regulation of apoptosis result in serious diseases such as cancer, autoimmunity, and neurodegeneration. During the last decade many of the molecular mechanisms of apoptosis signaling have been examined and elucidated. A systemic understanding of apoptosis is, however, still missing. To address the complexity of apoptotic signaling we subdivided this system into subsystems of different information qualities. A new approach for sensitivity analysis within the mathematical model was key for the identification of critical system parameters and two essential system properties: modularity and robustness. Our model describes the regulation of apoptosis on a systems level and resolves the important question of a threshold mechanism for the regulation of apoptosis
    Type of Publication: Journal article published
    PubMed ID: 15364960
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