Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas-associated death domain protein (FADD), caspase-8-related protein (Casper), and caspase-8 are components of the tumor necrosis factor receptor type 1 (TNF-R1) and Fas signaling complexes that are involved in TNF-R1- and Fas-induced apoptosis. Here we show that overexpression of FADD and Casper potently activates NF-kappaB. In the presence of caspase inhibitors, overexpression of caspase-8 also activates NF-kappaB. A caspase-inactive point mutant, caspase-8(C360S), activates NF-kappaB as potently as wild-type caspase-8, suggesting that caspase-8-induced apoptosis and NF-kappaB activation are uncoupled. NF-kappaB activation by FADD and Casper is inhibited by the caspase-specific inhibitors crmA and BD-fmk, suggesting that FADD- and Casper-induced NF-kappaB activation is mediated by caspase-8. FADD, Casper, and caspase-8-induced NF-kappaB activation are inhibited by dominant negative mutants of TRAF2, NIK, IkappaB kinase alpha, and IkappaB kinase beta. A dominant negative mutant of RIP inhibits FADD- and caspase-8-induced but not Casper-induced NF-kappaB activation. A mutant of Casper and the caspase-specific inhibitors crmA and BD-fmk partially inhibit TNF-R1-, TRADD, and TNF-induced NF-kappaB activation, suggesting that FADD, Casper, and caspase-8 function downstream of TRADD and contribute to TNF-R1-induced NF-kappaB activation. Moreover, activation of caspase-8 results in proteolytic processing of NIK, which is inhibited by crmA. When overexpressed, the processed fragments of NIK do not activate NF-kappaB, and the processed C-terminal fragment inhibits TNF-R1-induced NF-kappaB activation. These data indicate that FADD, Casper, and pro-caspase-8 are parts of the TNF-R1-induced NF-kappaB activation pathways, whereas activated caspase-8 can negatively regulate TNF-R1-induced NF-kappaB activation by proteolytically inactivating NIK.
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PMID:Activation of NF-kappaB by FADD, Casper, and caspase-8. 1075 78

The activation of nuclear factor kappaB (NF-kappa B) plays a pivotal role in the regulation of tumor necrosis factor (TNF)-mediated apoptosis. However, little is known about the regulation of TNF-mediated apoptosis by other signaling pathways or growth factors. Here, unexpectedly, we found that bone morphogenetic protein (BMP)-2 and BMP-4 inhibited TNF-mediated apoptosis by inhibition of caspase-8 activation in C2C12 cells, a pluripotent mesenchymal cell line that has the potential to differentiate into osteoblasts depending on BMP stimulation. Utilizing both a trans-dominant IkappaBalpha inhibitor of NF-kappaB expressed in C2C12 cells and IkappaB kinase beta-deficient embryonic mouse fibroblast, we show that BMP-mediated survival was independent of NF-kappaB activation. Rather, the antiapoptotic activity of BMPs functioned through the Smad signaling pathway. Thus, these findings provide the first report of a BMP/Smad signaling pathway that can inhibit TNF-mediated apoptosis, independent of the prosurvival activity of NF-kappaB. Our results suggest that BMPs not only stimulate osteoblast differentiation but can also promote cell survival during the induction of bone formation, offering new insight into the biological functions of BMPs.
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PMID:Suppression of tumor necrosis factor-mediated apoptosis by nuclear factor kappaB-independent bone morphogenetic protein/Smad signaling. 1150 May 9

Signals emanating from receptors of the tumor necrosis factor/nerve growth factor (TNF/NGF) family control practically all aspects of immune defense and, as such, constitute potential targets for therapeutic intervention through rational drug design. Indeed, arrest of these signals by blocking ligand-receptor interactions enables effective suppression of a variety of activities that are implicated in various pathologies, such as T and B lymphocyte activation and growth, inflammation, fibroblast proliferation, and cell death. To be therapeutically useful, however, inhibition of signaling should be restricted by determinants of specificity, at least to the same degree observed when blocking activation of individual receptors. In spite of their broad range of functions, receptors of the TNF/NGF family are known to activate just a few signaling pathways. Of these, the most extensively studied are the activation of the caspase protease cascade, which leads to cell death, and the activation of NF-kappaB (nuclear factor-kappaB) transcription factors through protein phosphorylation cascades. Until recently, most studies of the two pathways have solely focused on the core signaling complexes that are shared by the different receptors: death-inducing complexes containing the cysteine proteases caspase-8 and caspase-10, bound to the adapter protein MORT1/FADD (mediator of receptor-induced toxicity/Fas-associated DD protein), and the NF-kappaB-activating complex, composed of the protein kinases IKK1 (IkappaB kinase 1) and IKK2 (IkappaB kinase 2) and the regulatory subunit NEMO (NF-kappaB essential modulator; the 'IKK signalosome'). Knowledge has begun to emerge of additional molecules and mechanisms that affect these basic signaling complexes and impose specificity on their function.
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PMID:How are the regulators regulated? The search for mechanisms that impose specificity on induction of cell death and NF-kappaB activation by members of the TNF/NGF receptor family. 1211 Jan 39

Arsenic can induce apoptosis and is an efficient drug for the treatment of acute promyelocytic leukemia. Currently, clinical studies are investigating arsenic as a therapeutic agent for a variety of malignancies. In this study, Hodgkin/Reed-Sternberg (HRS) cell lines served as model systems to characterize the role of nuclear factor-kappaB (NF-kappaB) in arsenic-induced apoptosis. Arsenic rapidly down-regulated constitutive IkappaB kinase (IKK) as well as NF-kappaB activity and induced apoptosis in HRS cell lines containing functional IkappaB proteins. In these cell lines, apoptosis was blocked by inhibition of caspase-8 and caspase-3-like activity. Furthermore, arsenic treatment down-regulated NF-kappaB target genes, including tumor necrosis factor-alphareceptor-associated factor 1 (TRAF1), c-IAP2, interleukin-13 (IL-13), and CCR7. In contrast, cell lines with mutated, functionally inactive IkappaB proteins or with a weak constitutive IKK/NF-kappaB activity showed no alteration of the NF-kappaB activity and were resistant to arsenic-induced apoptosis. A direct role of the NF-kappaB pathway in arsenic-induced apoptosis is shown by transient overexpression of NF-kappaB-p65 in L540Cy HRS cells, which protected the cells from arsenic-induced apoptosis. In addition, treatment of NOD/SCID mice with arsenic trioxide induced a dramatic reduction of xenotransplanted L540Cy Hodgkin tumors concomitant with NF-kappaB inhibition. We conclude that inhibition of NF-kappaB contributes to arsenic-induced apoptosis. Furthermore, pharmacologic inhibition of the IKK/NF-kappaB activity might be a powerful treatment option for Hodgkin lymphoma.
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PMID:Inhibition of NF-kappaB essentially contributes to arsenic-induced apoptosis. 1267 92

Fas-associated factor-1 (FAF1) is a Fas-binding pro-apoptotic protein that is a component of the death-inducing signaling complex in Fas-mediated apoptosis. Here, we show that FAF1 is involved in negative regulation of NF-kappaB activation. Overexpression of FAF1 decreased the basal level of NF-kappaB activity in 293 cells. NF-kappaB activation induced by tumor necrosis factor (TNF)-alpha, interleukin-1beta, and lipopolysaccharide was also inhibited by FAF1 overexpression. Moreover, FAF1 suppressed NF-kappaB activation induced by transducers of diverse NF-kappaB-activating signals such as TNF receptor-associated factor-2 and -6, MEKK1, and IkappaB kinase-beta as well as NF-kappaB p65, one of the end point molecules in the NF-kappaB activation pathway, suggesting that NF-kappaB p65 might be a target molecule upon which FAF1 acts. Subsequent study disclosed that FAF1 physically interacts with NF-kappaB p65 and that the binding domain of FAF1 is the death effector domain (DED)-interacting domain (amino acids 181-381), where DEDs of the Fas-associated death domain protein and caspase-8 interact. The NF-kappaB activity-modulating potential of FAF1 was also mapped to the DED-interacting domain. Finally, overexpression of FAF1 prevented translocation of NF-kappaB p65 into the nucleus and decreased its DNA-binding activity upon TNFalpha treatment. This study presents a novel function of FAF1, in addition to the previously known function as a component of the Fas death-inducing signaling complex, i.e. NF-kappaB activity suppressor by cytoplasmic retention of NF-kappaB p65 via physical interaction.
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PMID:Fas-associated factor-1 inhibits nuclear factor-kappaB (NF-kappaB) activity by interfering with nuclear translocation of the RelA (p65) subunit of NF-kappaB. 1460 Jan 57

Toll-like receptor-3 is critically involved in host defense against viruses through induction of type I interferons (IFNs). Recent studies suggest that a Toll/interleukin-1 receptor domain-containing adapter protein (TRIF) and two protein kinases (TANK-binding kinase-1 (TBK1) and IkappaB kinase (IKK)-epsilon) are critically involved in Toll-like receptor-3-mediated IFN-beta production through activation of IFN regulatory factor (IRF)-3 and IRF-7. In this study, we demonstrate that TRIF interacts with both IRF-7 and IRF-3. In addition to TBK1 and IKKepsilon, our results indicate that IKKbeta can also phosphorylate IRF-3 and activate the IFN-stimulated response element. TRIF-induced IRF-3 and IRF-7 activation was mediated by TBK1 and its downstream kinases IKKbeta and IKKepsilon. TRIF induced NF-kappaB activation through an IKKbeta- and tumor necrosis factor receptor-associated factor-6-dependent (but not TBK1- and IKKepsilon-dependent) pathway. In addition, TRIF also induced apoptosis through a RIP/FADD/caspase-8-dependent and mitochondrion-independent pathway. Furthermore, our results suggest that the TRIF-induced IFN-stimulated response element and NF-kappaB activation and apoptosis pathways are uncoupled and provide a molecular explanation for the divergent effects induced by the adapter protein TRIF.
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PMID:Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. 1473 3

The tumor necrosis factor (TNF) ligand-receptor system plays an essential role in apoptosis that contributes to secondary damage after traumatic brain injury (TBI). TNF also stimulates inflammation by activation of gene transcription through the IkappaB kinase (IKK)/NF-kappaB and JNK (c-Jun N-terminal protein kinase)/AP-1 signaling cascades. The mechanism by which TNF signals between cell death and survival and the role of receptor localization in the activation of downstream signaling events are not fully understood. Here, TNF receptor 1 (TNFR1) signaling complexes in lipid rafts were investigated in the cerebral cortex of adult male Sprague Dawley rats subjected to moderate (1.8-2.2 atmospheres) fluid-percussion TBI and naive controls. In the normal rat cortex, a portion of TNFR1 was present in lipid raft microdomains, where it associated with the adaptor proteins TRADD (TNF receptor-associated death domain), TNF receptor-associated factor-2 (TRAF-2), the Ser/Thr kinase RIP (receptor-interacting protein), TRAF1, and cIAP-1 (cellular inhibitor of apoptosis protein-1), forming a survival signaling complex. Moderate TBI resulted in rapid recruitment of TNFR1, but not TNFR2 or Fas, to lipid rafts and induced alterations in the composition of signaling intermediates. TNFR1 and TRAF1 were polyubiquitinated in lipid rafts after TBI. Subsequently, the signaling complex contained activated caspase-8, thus initiating apoptosis. In addition, TBI caused a transient activation of NF-kappaB, but receptor signaling interacting proteins IKKalpha and IKKbeta were not detected in raft-containing fractions. Thus, redistribution of TNFR1 in lipid rafts and nonraft regions of the plasma membrane may regulate the diversity of signaling responses initiated by these receptors in the normal brain and after TBI.
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PMID:Tumor necrosis factor receptor 1 and its signaling intermediates are recruited to lipid rafts in the traumatized brain. 1559 Sep 16

Fas-associated death-domain protein (FADD) is an adaptor molecule that links death receptors to caspase-8 in many cell types including cardiomyocytes (CMs). Although FADD has previously been reported to play an important role in CM apoptosis, the effect of FADD on CM NF-kappaB signaling, which is a proinflammatory pathway, has not been delineated. To investigate the role of FADD in CM NF-kappaB activation, we utilized adenoviral gene transfer of wild-type FADD and a truncation mutant that lacks the death-effector domain (FADD-DED) in rat CMs in vitro TNF-alpha activated NF-kappaB in CMs as demonstrated by phosphorylation and degradation of inhibitory-kappaB (IkappaB)-alpha-enhanced nuclear p65 and NF-kappaB DNA-binding activity as well as increased mRNA for the NF-kappaB-dependent adhesion molecule VCAM-1 (19 +/- 4.1-fold) as measured by quantitative RT-PCR. Gene transfer of FADD inhibited TNF-alpha-induced IkappaB-alpha phosphorylation, decreased p65 nuclear translocation and NF-kappaB DNA-binding activity, and reduced VCAM-1 transcript levels by 53-65%. Interestingly, FADD-DED exhibited a similar but weaker inhibitory effect on NF-kappaB activation. The effects of FADD on NF-kappaB were cell-type specific. FADD expression also inhibited TNF-alpha-mediated NF-kappaB activation in human endothelial cells but not in rat pulmonary artery smooth muscle cells. In contrast, FADD expression actually activated NF-kappaB in human embryonic kidney (HEK)-293 cells. In CMs, FADD inhibited NF-kappaB activation as well as phosphorylation of IkappaB-alpha and IkappaB kinase (IKK)-beta in response to cytokine stimulation or expression of the upstream kinases NF-kappaB-inducing kinase and IKK-beta. These data demonstrate that FADD inhibits NF-kappaB activation in CMs, and this inhibition likely occurs at the level of phosphorylation and activation of IKK-beta.
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PMID:Fas-associated death-domain protein inhibits TNF-alpha mediated NF-kappaB activation in cardiomyocytes. 1598 38

Primary effusion lymphomas (PELs) characterized by infection with the Kaposi's sarcoma herpesvirus (KSHV; also called human herpesvirus 8) depend on the expression of the viral FADD-like interleukin-1-beta-converting enzyme (FLICE)/caspase-8-inhibitory protein (vFLIP) for their survival. This effect is achieved by activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Tumour necrosis factor (TNF) receptor-associated factors (TRAFs) are direct mediators of NF-kappaB signalling by TNF family receptors and the Epstein-Barr virus oncoprotein latent membrane protein 1 and so we assessed the role of TRAFs in signalling by vFLIP. Here, we report the identification of a TRAF-interacting motif (PYQLT) in vFLIP, which is not present in other FLIP molecules. We show that vFLIP directly binds to TRAF2 in vitro and in PEL cells. TRAF2 and TRAF3 are required for induction of NF-kappaB and associated cell survival, as well as Jun amino-terminal kinase phosphorylation by vFLIP, whereas TRAF1, TRAF5 and TRAF6 are dispensable. Mutations in the P93 or Q95 amino acids within the TRAF-interacting motif of vFLIP abolish its ability to bind to TRAF2 and to signal to NF-kappaB. TRAF2, but not TRAF3, mediates the association of vFLIP with the IkappaB kinase complex. These data indicate that vFLIP uses TRAF2 and TRAF3 for signalling to NF-kappaB, which is crucial for KSHV-associated lymphomagenesis.
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PMID:The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. 1631 16

The activation of NF-kappaB by T-cell receptor (TCR) signaling is critical for T-cell activation during the adaptive immune response. CARD11 is a multidomain adapter that is required for TCR signaling to the IkappaB kinase (IKK) complex. During TCR signaling, the region in CARD11 between the coiled-coil and PDZ domains is phosphorylated by protein kinase Ctheta (PKCtheta) in a required step in NF-kappaB activation. In this report, we demonstrate that this region functions as an inhibitory domain (ID) that controls the association of CARD11 with multiple signaling cofactors, including Bcl10, TRAF6, TAK1, IKKgamma, and caspase-8, through an interaction that requires both the caspase recruitment domain (CARD) and the coiled-coil domain. Consistent with the ID-mediated control of their association, we demonstrate that TRAF6 and caspase-8 associate with CARD11 in T cells in a signal-inducible manner. Using an RNA interference rescue assay, we demonstrate that the CARD, linker 1, coiled-coil, linker 3, SH3, linker 4, and GUK domains are each required for TCR signaling to NF-kappaB downstream of ID neutralization. Requirements for the CARD, linker 1, and coiled-coil domains in signaling are consistent with their roles in the association of CARD11 with Bcl10, TRAF6, TAK1, caspase-8, and IKKgamma. Using Bcl10- and MALT1-deficient cells, we show that CARD11 can recruit signaling cofactors independently of one another in a signal-inducible manner.
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PMID:The protein kinase C-responsive inhibitory domain of CARD11 functions in NF-kappaB activation to regulate the association of multiple signaling cofactors that differentially depend on Bcl10 and MALT1 for association. 1862 28


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