28 results on '"Death domain"'
Search Results
2. The death domain protein p84N5, but not the short isoform p84N5s, is cell cycle-regulated and shuttles between the nucleus and the cytoplasm
- Author
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Gasparri, Fabio, Sola, Francesco, Locatelli, Giuseppe, and Muzio, Marta
- Subjects
- *
CELL death , *APOPTOSIS , *TUMORS , *NEUROBLASTOMA - Abstract
P84N5 is a death domain containing protein that interacts with the tumor suppressor retinoblastoma protein and induces apoptosis. We cloned and characterized two novel alternatively spliced versions of p84N5. The p84N5 short isoform (p84N5s) lacks the death domain and does not induce apoptosis. We showed that p84N5, but not p84N5s, is cell cycle regulated. We found that p84N5-GFP chimera can rapidly shuttle between the nucleus and the cytoplasm. Taken together, these observations suggest that p84N5 may transmit signals from the nucleus to cytoplasmic effectors. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
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3. Functional signaling of membrane-bound TL1A induces IFN-γ expression
- Author
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Stephan R. Targan, Rivkah Gonsky, Eva Biener-Ramanujan, and Brian Ko
- Subjects
Membrane bound ,T-Lymphocytes ,Biophysics ,Endogeny ,Biochemistry ,Structural Biology ,Genetics ,Secretion ,Receptor ,IFN-γ ,Receptors, Tumor Necrosis Factor, Member 25 ,Molecular Biology ,Death domain ,biology ,Membrane-bound TL1A ,Interleukin-18 ,Death domain receptor 3 ,Cell Biology ,Interleukin-12 ,Molecular biology ,Cellular Structures ,Transmembrane protein ,Cell biology ,TL1A signaling ,biology.protein ,Tumor necrosis factor alpha ,Antibody ,Signal Transduction - Abstract
TL1A, a TNF member implicated in autoimmune diseases, is a transmembrane protein that is processed to release soluble TL1A (TL1A-S). TL1A-S induces a Th1 response, although the functional significance of membrane-bound TL1A (TL1A-M) remains unknown. We generated TL1A-M expression in HEK-293 cells capable of binding DR3-Fc. Co-incubating IL-12/IL-18-primed CD4(+) T cells with HEK-293 cells expressing TL1A-M induced 3-fold increase in IFN-gamma that was blocked by anti-TL1A Ab. These results demonstrate that TL1A-M can bind death domain receptor 3 (DR3) through cell-cell contact to induce downstream IFN-gamma secretion enhancement. Anti-TL1A antibodies designed to treat immune diseases should be verified to block both endogenous TL1A forms.
- Published
- 2010
4. BS69 negatively regulates the canonical NF-κB activation induced by Epstein-Barr virus-derived LMP1
- Author
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Akihiro Mizushima, Tadashi Matsuda, Yuichi Sekine, Teruhito Yasui, Kenji Oritani, Masahiro Fujimuro, Osamu Ikeda, Asuka Nanbo, and Ryuta Muromoto
- Subjects
TNFR-associated death domain protein ,Immunoprecipitation ,Biophysics ,Cell Cycle Proteins ,medicine.disease_cause ,Models, Biological ,Biochemistry ,NF-κB ,Epstein–Barr virus ,Viral Matrix Proteins ,chemistry.chemical_compound ,EBV ,Structural Biology ,Latent membrane protein 1 ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Molecular Biology ,Cells, Cultured ,LMP1 ,Death domain ,Interleukin-6 ,Kinase ,Chemistry ,NF-kappa B ,Cell Biology ,BS69 ,TRADD ,TNF Receptor-Associated Death Domain Protein ,Cell biology ,DNA-Binding Proteins ,stomatognathic diseases ,Gene Expression Regulation ,Microscopy, Fluorescence ,Cancer research ,Tumor necrosis factor alpha ,Signal transduction ,Carrier Proteins ,Co-Repressor Proteins ,HeLa Cells ,Signal Transduction - Abstract
Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) activates NF-κB signaling pathways through the two C-terminal regions, CTAR1 and CTAR2. BS69 has previously been shown to be involved in LMP1-induced c-Jun N-terminal kinase activation through CTAR2 by interacting with tumor necrosis factor (TNFR) receptor-associated factor 6. In the present study, our manipulation of BS69 expression clearly indicates that BS69 negatively regulates LMP1-mediated NF-κB activation and up-regulates IL-6 mRNA expression and IκB degradation. Our immunoprecipitation experiments suggest that BS69 decreases complex formation between LMP1 and TNFR-associated death domain protein (TRADD). Structured summary MINT- 7032462 : LMP1 (uniprotkb: P03230 ) physically interacts (MI: 0218 ) with TRADD (uniprotkb: Q15628 ) by anti bait coimmunoprecipitation (MI: 0006 ) MINT- 7032451 : BS69 (uniprotkb: Q15326 ) and LMP1 (uniprotkb: P03230 ) colocalize (MI: 0403 ) by fluorescence microscopy (MI: 0416 ) MINT- 7032478 : LMP1 (uniprotkb: P03230 ) physically interacts (MI: 0218 ) with BRAM1 (uniprotkb: Q15326 ) by anti bait coimmunoprecipitation (MI: 0006 )
- Published
- 2009
5. The death domain-associated protein modulates activity of the transcription co-factor Skip/NcoA62
- Author
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Jun Tang, Xiaolu Yang, and Howard Y. Chang
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Interaction ,Blotting, Western ,Biophysics ,Biology ,Biochemistry ,Cell Line ,Serine ,Skip ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Death-associated protein 6 ,Daxx ,Structural Biology ,Transcription (biology) ,Genetics ,Transcriptional regulation ,Animals ,Humans ,NcoA62 ,Phosphorylation ,Molecular Biology ,Cellular localization ,Adaptor Proteins, Signal Transducing ,DNA Primers ,030304 developmental biology ,Death domain ,0303 health sciences ,Base Sequence ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Cell Biology ,Cell biology ,Apoptosis ,030220 oncology & carcinogenesis ,Electrophoresis, Polyacrylamide Gel ,Carrier Proteins ,Transcription ,Co-Repressor Proteins ,Molecular Chaperones - Abstract
Death domain-associated protein (Daxx) regulates both transcription and apoptosis. The role of Daxx in transcription is not well understood. Here, we show that Daxx interacts with Skip/NcoA62, a transcription cofactor that modulates the activity of oncoproteins including Ski and NotchIC. Daxx strongly binds with Skip both in vitro and in mammalian cells. This interaction is mediated by the PAH2 domain of Daxx and the highly conserved SNW domain of Skip. Daxx partially co-localizes with Skip in vivo and changes the cellular distribution of Skip. In addition, Skip represses transcription when tethered to a promoter, and Daxx antagonizes this activity. Furthermore, Skip is phosphorylated at serine 224 in its SNW domain. These results suggest a novel function of Daxx in transcription regulation through alteration of the cellular localization of Skip.
- Published
- 2005
6. Receptor interacting protein is ubiquitinated by cellular inhibitor of apoptosis proteins (c-IAP1 and c-IAP2) in vitro
- Author
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Tae H. Lee, Jong Bok Yoon, and Sun Mi Park
- Subjects
endocrine system ,TRAF2 ,endocrine system diseases ,Ubiquitin-Protein Ligases ,Immunoblotting ,Receptor interacting protein ,Biophysics ,Apoptosis ,Transfection ,Cellular inhibitor of apoptosis protein ,Inhibitor of apoptosis ,digestive system ,Biochemistry ,Receptors, Tumor Necrosis Factor ,Cell Line ,Inhibitor of Apoptosis Proteins ,Mice ,Tumor necrosis factor-α receptor 1-associated factor 2 ,Ubiquitin ,Structural Biology ,Genetics ,Protein biosynthesis ,Animals ,Humans ,Receptor ,Molecular Biology ,Death domain ,chemistry.chemical_classification ,DNA ligase ,biology ,Chemistry ,Ubiquitination ,Proteins ,nutritional and metabolic diseases ,Cell Biology ,Molecular biology ,Baculoviral IAP Repeat-Containing 3 Protein ,Recombinant Proteins ,Protein Structure, Tertiary ,Cell biology ,Proteasome ,Protein Biosynthesis ,Receptor-Interacting Protein Serine-Threonine Kinases ,biology.protein ,Gene Deletion - Abstract
Receptor interacting protein (RIP) is recruited to tumor necrosis factor-alpha receptor 1 (TNFR1) complex upon stimulation and plays a crucial role in the receptor-mediated NF-kappaB activation. Among the components of the TNFR1 complex are proteins that possess ubiquitin-protein isopeptide ligase (E3) activities, such as TNFR1-associated factor 2 (TRAF2), cellular inhibitor of apoptosis proteins (c-IAPs) namely, c-IAP1 and c-IAP2. Here, we showed that ectopically expressed RIP is ubiquitinated, and either the intermediate or death domain of RIP is required for this modification. Expression of c-IAP1 and c-IAP2 decreased the steady-state level of RIP, which was blocked by inhibition of the 26S proteasome. RIP degradation requires intact c-IAP2 containing the RING domain. Our in vitro ubiquitination assay revealed that while TRAF2 had no effect, both c-IAP1 and c-IAP2-mediated RIP ubiquitination with similar efficiency, indicating that c-IAPs can function as E3 toward RIP.
- Published
- 2004
7. Hinge sequences as signaling agents?
- Author
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Boguslaw Stec
- Subjects
Models, Molecular ,Calmodulin ,Amino Acid Motifs ,Biophysics ,Hinge ,Biology ,Bioinformatics ,Biochemistry ,Hinge location ,Structural Biology ,H-predictor ,Genetics ,fas Receptor ,Molecular Biology ,Death domain ,Extrinsic apoptotic pathway ,Protein Stability ,Cell Biology ,Fas receptor ,Signaling ,Protein Structure, Tertiary ,Unexpected finding ,Structural Homology, Protein ,biology.protein ,Neuroscience ,Signal Transduction - Abstract
We report an unexpected finding of common structural principles in two unrelated signaling systems: the FAS death domain transformation that initializes the extrinsic apoptotic pathway and signaling by calmodulin bending. The location and design of the hinge is postulated to be a general principle for creating potential signaling event. We suggest that already existing tool can predict the existence of such a hinge and formulate the hypothesis that the internal instabilities designed into the hinge sequences are necessary devices in effective signaling events.
- Published
- 2012
8. Identification of a basic surface area of the FADD death effector domain critical for apoptotic signaling
- Author
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Damir Bozic, Andreas Kohl, Christophe Briand, Jürg Tschopp, Jean-Luc Bodmer, Oliver Zerbe, Markus Kaufmann, and Markus G. Grütter
- Subjects
Models, Molecular ,Protein Conformation ,Fas-Associated Death Domain Protein ,Molecular Sequence Data ,Fas-associated death domain ,Mutant ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Biophysics ,Apoptosis ,Homotypic interaction ,Caspase 8 ,Biochemistry ,Structural Biology ,Death inducing signaling complex ,Genetics ,Humans ,Amino Acid Sequence ,FADD ,Death effector domain ,Molecular Biology ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Death domain ,Binding Sites ,biology ,Caspase 3 ,Effector ,Intracellular Signaling Peptides and Proteins ,Cell Biology ,Inhibitor protein ,Protein Structure, Tertiary ,Cell biology ,Caspases ,Mutation ,Cellular FLICE inhibitor protein ,Death-inducing signaling complex ,biology.protein ,Carrier Proteins ,Caspase-8 ,Signal Transduction - Abstract
Death effector domains (DEDs) are protein–protein interaction domains found in the death inducing signaling complex (DISC). Performing a structure-based alignment of all DED sequences we identified a region of high diversity in α-helix 3 and propose a classification of DEDs into class I DEDs typically containing a stretch of basic residues in the α-helix 3 region whereas DEDs of class II do not. Functional assays using mutants of Fas-associated death domain revealed that this basic region influences binding and recruitment of caspase-8 and cellular FLICE inhibitor protein to the DISC.
- Published
- 2002
9. A docking model of key components of the DISC complex: death domain superfamily interactions redefined
- Author
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Christian Weber and Claudius Vincenz
- Subjects
Models, Molecular ,Fas-Associated Death Domain Protein ,Molecular Sequence Data ,Biophysics ,Apoptosis ,Plasma protein binding ,Biology ,Death domain superfamily ,Caspase 8 ,Biochemistry ,Protein Structure, Secondary ,Death domain ,Structural Biology ,Genetics ,Animals ,Humans ,Amino Acid Sequence ,fas Receptor ,FADD ,Death effector domain ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Sequence Homology, Amino Acid ,Cell Biology ,Fas receptor ,Caspase recruitment domain ,Caspase 9 ,Cell biology ,Docking model ,Caspases ,Death-inducing signaling complex ,biology.protein ,Signal transduction ,Carrier Proteins ,Dimerization ,Protein Binding - Abstract
Apoptosis is mediated by a highly regulated signal transduction cascade that eventually leads to precisely directed cell death. The death-inducing signaling complex (DISC), composed of Fas, FADD, and caspase-8, is an apical signaling complex that mediates receptor-induced apoptosis. We have docked the experimentally determined structures of the Fas and FADD death domains into a model of a partial DISC signaling complex. The arrangement of Fas and FADD was determined using the interaction modes of the two heterodimer crystal structures determined to date, Pelle/Tube and Apaf-1/procaspase-9. The proposed model reveals that both interactions can be accommodated in a single multimeric complex. Importantly, the model is consistent with reported site-directed mutagenesis data indicating residues throughout the domain are critical for function. These results imply that members of the death domain superfamily have the potential for multivalent interactions, offering novel possibilities for regulation of apoptotic signaling.
- Published
- 2001
10. N-Acetylcysteine suppresses TNF-induced NF-κB activation through inhibition of IκB kinases
- Author
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Shin Ichi Oka, Hajime Hirata, Keiko Kamata, Hideaki Kamata, and Hitoshi Yagisawa
- Subjects
IκB kinase ,Tumor necrosis factor ,Biophysics ,Protein Serine-Threonine Kinases ,Biochemistry ,Receptors, Tumor Necrosis Factor ,Redox ,Structural Biology ,Genetics ,Humans ,Nuclear factor κB ,Phosphorylation ,Molecular Biology ,Death domain ,Cell Nucleus ,Protein-Serine-Threonine Kinases ,Tumor Necrosis Factor-alpha ,Kinase ,Chemistry ,NF-kappa B ,I-Kappa-B Kinase ,Proteins ,Biological Transport ,Free Radical Scavengers ,Cell Biology ,TNF Receptor-Associated Factor 2 ,NFKB1 ,TNF Receptor-Associated Factor 1 ,Molecular biology ,Acetylcysteine ,I-kappa B Kinase ,Cell biology ,Dithiothreitol ,N-Acetyl-L-cysteine ,Tumor necrosis factor alpha ,HeLa Cells - Abstract
Here, we used a reductant, N-acetyl-L-cysteine (NAC), to investigate the redox-sensitive step(s) in the signalling pathway from the tumor necrosis factor (TNF) receptor to nuclear factor kappaB (NF-kappaB). We found that NAC suppressed NF-kappaB activation triggered by TNF or by overexpression of either the TNF receptor-associated death domain protein, TNF receptor-associated factor 2, NF-kappaB-inducing kinase (NIK), or IkappaB kinases (IKKalpha and IKKbeta). NAC also suppressed the TNF-induced activation of IKKalpha and IKKbeta, phosphorylation and degradation of IkappaB, and nuclear translocation of NF-kappaB. Furthermore, NAC suppressed the activation of IKKalpha and IKKbeta triggered by the overexpression of NIK. These results indicate that IKKalpha and IKKbeta are subject to redox regulation in the cells, and that NAC inhibits NF-kappaB activation through the suppression of these kinases.
- Published
- 2000
11. Activation of p42/p44 mitogen-activated protein kinases (MAPK) and p38 MAPK by tumor necrosis factor (TNF) is mediated through the death domain of the 55-kDa TNF receptor
- Author
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Veronique Vandevoorde, Elke Boone, Gert De Wilde, and Guy Haegeman
- Subjects
MAPK/ERK pathway ,endocrine system ,Tumor necrosis factor ,Fibrosarcoma ,p38 mitogen-activated protein kinases ,Molecular Sequence Data ,Biophysics ,Vascular endothelial growth inhibitor ,p38 Mitogen-Activated Protein Kinases ,environment and public health ,Biochemistry ,Receptors, Tumor Necrosis Factor ,Mice ,Death domain ,Antigens, CD ,Structural Biology ,Tumor Cells, Cultured ,Genetics ,Animals ,Amino Acid Sequence ,Protein kinase A ,Molecular Biology ,DNA Primers ,Base Sequence ,biology ,Tumor Necrosis Factor-alpha ,Kinase ,Chemistry ,Cell Biology ,Mitogen-activated protein kinase ,Recombinant Proteins ,Signaling ,Cell biology ,Enzyme Activation ,enzymes and coenzymes (carbohydrates) ,Receptors, Tumor Necrosis Factor, Type I ,Calcium-Calmodulin-Dependent Protein Kinases ,biology.protein ,Tumor necrosis factor alpha ,Mitogen-Activated Protein Kinases ,biological phenomena, cell phenomena, and immunity ,Receptor - Abstract
In the mouse fibrosarcoma cell line L929sA, tumor necrosis factor (TNF) stimulates activation of the stress-responsive p38 mitogen-activated protein kinase (MAPK), as well as the classical p42 and p44 MAPK. TNF signaling can be mediated by p55 or p75 TNF receptors. Here, we demonstrate that TNF-R55 is sufficient to activate p42/p44 MAPK and p38 MAPK. Moreover, by expressing different membrane-bound or purely cytoplasmic truncations of TNF-R55, we show that the intracellular death domain of TNF-R55 is the crucial domain involved. The cytoplasmic membrane-proximal region of TNF-R55, known to induce neutral sphingomyelinase activation, is not required for activation of p38 MAPK or p42/p44 MAPK.
- Published
- 1998
12. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling
- Author
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Jian Ni, Vishva M. Dixit, Guohua Pan, Guo-liang Yu, and Ying-Fei Wei
- Subjects
Decoy receptor ,Molecular Sequence Data ,Biophysics ,Apoptosis ,Biology ,Biochemistry ,Receptors, Tumor Necrosis Factor ,TNF-Related Apoptosis-Inducing Ligand ,Death domain ,Structural Biology ,Genetics ,Enzyme-linked receptor ,Humans ,Tissue Distribution ,Amino Acid Sequence ,Decoy receptors ,Receptor ,Molecular Biology ,Cells, Cultured ,Membrane Glycoproteins ,Sequence Homology, Amino Acid ,Tumor Necrosis Factor-alpha ,Membrane Proteins ,Cell Biology ,Cell biology ,Tumor Necrosis Factor Decoy Receptors ,TRAIL receptor ,Ectopic expression ,Tumor necrosis factor receptor ,Apoptosis Regulatory Proteins ,Sequence Alignment ,Intracellular - Abstract
TRAIL/Apo-2L induces rapid apoptosis of a variety of tumor cell lines. A family of tumor necrosis factor receptor-related molecules have been identified as receptors for TRAIL. Herein, we report the identification of another member of the TRAIL receptor family, TRUNDD (TRAIL receptor with a truncated death domain). The TRUNDD transcript was detected in multiple human tissues. TRUNDD is highly homologous to all known TRAIL receptors and has an extracellular TRAIL-binding domain but lacks a functional intracellular death domain and does not induce apoptosis. Consistent with an inhibitory role, ectopic expression of TRUNDD attenuated TRAIL-induced apoptosis in mammalian cells.
- Published
- 1998
13. Interaction of Fas(Apo-1/CD95) with proteins implicated in the ubiquitination pathway
- Author
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Pascal Schneider, Kay Hofmann, Karin Becker, Jürg Tschopp, and Chantal Mattmann
- Subjects
Molecular Sequence Data ,Biophysics ,Sequence Homology ,Apoptosis ,Ubiquitin-conjugating enzyme ,Biology ,Transfection ,Biochemistry ,Fas ligand ,Ligases ,Mice ,Structural Biology ,Fas(Apo-1/CD95) ,Genetics ,Animals ,Humans ,Amino Acid Sequence ,fas Receptor ,Ubiquitins ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Death domain ,Binding Sites ,Ubiquitin ,Intracellular Signaling Peptides and Proteins ,Yeast two-hybrid ,Signal transducing adaptor protein ,Cell Biology ,Fas receptor ,Molecular biology ,Cell biology ,Ubiquitin-Conjugating Enzymes ,Fas signaling pathway ,Signal transduction ,Apoptosis Regulatory Proteins ,Carrier Proteins ,HeLa Cells ,Signal Transduction - Abstract
Fas(Apo-1/CD95), a receptor belonging to the tumor necrosis factor receptor family, induces apoptosis when triggered by Fas ligand. Upon its activation, the cytoplasmic domain of Fas binds several proteins which transmit the death signal. We used the yeast two-hybrid screen to isolate Fas-associated proteins. Here we report that the ubiquitin-conjugating enzyme UBC9 binds to Fas at the interface between the death domain and the membrane-proximal region of Fas. This interaction is also seen in vivo. UBC9 transiently expressed in HeLa cells bound to the co-expressed cytoplasmic segment of Fas. FAF1, a Fas-associated protein that potentiates apoptosis (Chu et al. (1996) Proc. Natl. Acad. Sci. USA 92, 11894–11898), was found to contain sequences similar to ubiquitin. These results suggest that proteins related to the ubiquitination pathway may modulate the Fas signaling pathway.
- Published
- 1997
14. Agonist antibody activates death receptor 6 downstream signaling involving TRADD recruitment
- Author
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Jingyun Li, Qiumei Du, Tingting Wang, Xiangyun Yin, Rui Hu, and Liguo Zhang
- Subjects
Agonist ,Small interfering RNA ,medicine.drug_class ,Biophysics ,Apoptosis ,Biochemistry ,Receptors, Tumor Necrosis Factor ,Death domain ,Structural Biology ,Genetics ,medicine ,Humans ,FADD ,DR6 ,Receptor ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,biology ,Chemistry ,Tumor Necrosis Factor-alpha ,NF-kappa B ,Antibodies, Monoclonal ,Cell Biology ,Ligand (biochemistry) ,TRADD ,TNF Receptor-Associated Death Domain Protein ,HEK293 Cells ,biology.protein ,Cancer research ,Agonist antibody ,Intracellular ,Signal Transduction - Abstract
Death receptor 6 (DR6) is a member of the death domain-containing receptors that belong to the TNFR superfamily. To date, the ligand for DR6 is still not clearly defined. Here, we developed a functional agonist monoclonal antibody (DQM3) against DR6, which bound to the first cysteine-rich domain. Importantly, DR6 signaling could be clearly activated by DQM3, which was dependent on its intracellular death domain. In addition, we demonstrated that the association between DR6 and TRADD was enhanced upon DQM3 stimulation and TRADD was involved in DR6-induced signaling activation. Taken together, our findings provide new insight into a novel mechanism by which DR6 induces downstream signaling in response to an agonist antibody.
- Published
- 2013
15. Distinct roles of TIR and non-TIR regions in the subcellular localization and signaling properties of MyD88
- Author
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Takahiro Horinouchi, Soichi Miwa, Arata Nishimoto, Emi Kajita, and Tadashi Nishiya
- Subjects
Yellow fluorescent protein ,Cytoplasm ,Protein Folding ,Biophysics ,Biochemistry ,digestive system ,Substrate Specificity ,Structural Biology ,TLR ,parasitic diseases ,Genetics ,Humans ,Tissue Distribution ,Molecular Biology ,Cells, Cultured ,Death domain ,Organelles ,Toll-like receptor ,Membrane Glycoproteins ,biology ,TIR domain ,Subcellular localization ,Toll-Like Receptors ,Signal transducing adaptor protein ,Receptors, Interleukin-1 ,hemic and immune systems ,Cell Biology ,Non-TIR region ,biochemical phenomena, metabolism, and nutrition ,MyD88 ,Transport protein ,Cell biology ,Protein Structure, Tertiary ,Protein Transport ,Myeloid Differentiation Factor 88 ,biology.protein ,Signal transduction ,Protein Binding ,Signal Transduction - Abstract
MyD88 is a cytoplasmic adaptor protein that is critical for Toll-like receptor (TLR) signaling. The subcellular localization of MyD88 is characterized as large condensed forms in the cytoplasm. The mechanism and significance of this localization with respect to the signaling function, however, are currently unknown. Here, we demonstrate that MyD88 localization depends on the entire non-TIR region and that the correct cellular targeting of MyD88 is indispensable for its signaling function. The Toll-interleukin I receptor-resistance (TIR) domain does not determine the subcellular localization, but it mediates interaction with specific TLRs. These findings reveal distinct roles for the TIR and non-TIR regions in the subcellular localization and signaling properties of MyD88.
- Published
- 2007
16. Thermodynamics and stability of the PAAD/DAPIN/PYRIN domain of IFI-16
- Author
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Frederic Pio and Kush Dalal
- Subjects
Models, Molecular ,Circular dichroism ,Protein Denaturation ,Protein Folding ,030303 biophysics ,Protein domain ,Molecular Sequence Data ,Biophysics ,Thermodynamics ,Biochemistry ,Pyrin domain ,Thermal denaturation ,Fluorescence ,Protein Structure, Secondary ,03 medical and health sciences ,Structural Biology ,Protein stability ,Genetics ,Humans ,Amino Acid Sequence ,Molecular Biology ,030304 developmental biology ,Death domain ,PAAD/DAPIN/PYRIN ,Helix bundle ,0303 health sciences ,Chemistry ,Spectrum Analysis ,Nuclear Proteins ,SUPERFAMILY ,Cell Biology ,Phosphoproteins ,Sequence identity ,Protein Structure, Tertiary ,Crystallography ,CARD domain - Abstract
The PAAD domain is a conserved domain recently identified in more than 35 human proteins that are involved in apoptosis and inflammatory signaling pathways. Structural studies have confirmed that this domain belongs to the death domain superfamily which includes PAAD/CARD/DED/DD families. Recently, the 3D structures determined by NMR of NALP1 and ASC PAAD domain, members of the PAAD family, have shown that it is composed of a 6 helix bundle as with other death domain family members. However, helix-3 in the solved structures is unordered in solution. In this study we compare the thermodynamic, folding and stability properties of different members of the PAAD and CARD families and investigate structural conformational changes induced by the helix inducers trifluoroethanol and SDS on the PAAD domain of IFI16 and on the CARD domain of RAIDD. We show that inside the PAAD and CARD families, members have similar thermodynamic properties, however, the ΔG of folding for PAAD and CARD members are, respectively, −1.4 and −5.5kcalmol−1. This difference is attributed to less alpha helical content for PAAD due to the unfolding of helix-3 that lowers bonded energy and increases disorder when compared to CARD members. Despite identical fold between PAAD and CARD families but limited sequence identity, there are striking differences in the thermodynamics of both families.
- Published
- 2006
17. The death domain protein p84N5, but not the short isoform p84N5s, is cell cycle-regulated and shuttles between the nucleus and the cytoplasm
- Author
-
Francesco Sola, Marta Muzio, Giuseppe Locatelli, and Fabio Gasparri
- Subjects
Cytoplasm ,Biophysics ,Apoptosis ,Cell Cycle Proteins ,Biochemistry ,Polymerase Chain Reaction ,Nucleus ,Retinoblastoma-like protein 1 ,Death domain ,Structural Biology ,Genetics ,p84N5 ,E2F1 ,Humans ,Nuclear protein ,Cell Cycle Protein ,Molecular Biology ,Cells, Cultured ,DNA Primers ,Cell Nucleus ,biology ,Base Sequence ,Retinoblastoma protein ,Nuclear Proteins ,RNA-Binding Proteins ,Cell Biology ,Cell cycle ,Molecular biology ,DNA-Binding Proteins ,Protein Transport ,biology.protein ,Alternative splicing - Abstract
P84N5 is a death domain containing protein that interacts with the tumor suppressor retinoblastoma protein and induces apoptosis. We cloned and characterized two novel alternatively spliced versions of p84N5. The p84N5 short isoform (p84N5s) lacks the death domain and does not induce apoptosis. We showed that p84N5, but not p84N5s, is cell cycle regulated. We found that p84N5-GFP chimera can rapidly shuttle between the nucleus and the cytoplasm. Taken together, these observations suggest that p84N5 may transmit signals from the nucleus to cytoplasmic effectors.
- Published
- 2004
18. Activation of a pro-apoptotic amplification loop through inhibition of NF-kappaB-dependent survival signals by caspase-mediated inactivation of RIP
- Author
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Fabio Martinon, Jürg Tschopp, Nils Holler, and Christelle Richard
- Subjects
Programmed cell death ,Death receptor ,Kinase ,Survival ,Tumor necrosis factor ,Cell Survival ,Biophysics ,Apoptosis ,Protein Serine-Threonine Kinases ,Biochemistry ,Models, Biological ,NF-κB ,chemistry.chemical_compound ,Jurkat Cells ,Structural Biology ,Genetics ,Tumor Cells, Cultured ,Humans ,Amino Acid Sequence ,fas Receptor ,Molecular Biology ,Caspase ,Death domain ,Binding Sites ,biology ,NF-kappa B ,Proteins ,Cell Biology ,Fas ,Fas receptor ,Recombinant Proteins ,chemistry ,RIP ,Caspases ,Receptor-Interacting Protein Serine-Threonine Kinases ,biology.protein ,Cancer research ,Mutagenesis, Site-Directed ,Cell activation ,Signal Transduction - Abstract
Death domain containing members of the tumor necrosis factor receptor (TNFR) superfamily can induce apoptosis or cell activation. However, the mechanisms by which these opposing programs are selected remain unclear. Frequently, NF-kappaB activation conveys protection against cell death. We show that the serine/threonine kinase RIP that is required for TNF-induced NF-kappaB activation is processed by caspase-8 into a dominant-negative (DN) fragment during death receptor-induced apoptosis, thereby leading to a blockade of NF-kappaB-mediated anti-apoptotic signals. Our results suggest that cleavage of RIP is part of an amplification loop which is triggered by Fas and most likely by other death receptors.
- Published
- 2000
19. Identification and functional characterization of DR6, a novel death domain-containing TNF receptor
- Author
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Jian Ni, Johannes H. Bauer, Ding Liu, Valsala Haridas, Claudius Vincenz, Guohua Pan, Shu-Xia Wang, Vishva M. Dixit, Guo-liang Yu, and Bharat B. Aggarwal
- Subjects
Death receptor ,Molecular Sequence Data ,Biophysics ,Inflammation ,Apoptosis ,Biology ,Biochemistry ,Receptors, Tumor Necrosis Factor ,Death domain ,Structural Biology ,Genetics ,medicine ,Tumor Cells, Cultured ,Humans ,Nuclear factor κB ,Amino Acid Sequence ,RNA, Messenger ,Cloning, Molecular ,Receptor ,Molecular Biology ,Base Sequence ,Sequence Homology, Amino Acid ,JNK Mitogen-Activated Protein Kinases ,NF-kappa B ,Cell Biology ,TRADD ,Transmembrane protein ,Cell biology ,Calcium-Calmodulin-Dependent Protein Kinases ,Ectopic expression ,Tumor necrosis factor alpha ,JNK ,medicine.symptom ,Mitogen-Activated Protein Kinases ,Tumor necrosis factor receptor ,Protein Binding - Abstract
Tumor nectosis factor (TNF) receptors are key players in inflammation and immune regulation. A new member of this family, termed death receptor-6 (DR6), has been identified. Like other death receptors, DR6 is a type I transmembrane receptor, possesses four extracellular cysteine-rich motifs and a cytoplasmic death domain. DR6 is expressed in most human tissues and abundant transcript was detected in heart, brain, placenta, pancreas, thymus, lymph node and several non-lymphoid cancer cell lines. DR6 interacts with TRADD, which has previously been shown to associate with TNFR1. Furthermore, ectopic expression of DR6 in mammalian cells induces apoptosis and activation of both NF-κB and JNK.
- Published
- 1998
20. The death domain motif found in Fas (Apo-1) and TNF receptor is present in proteins involved in apoptosis and axonal guidance
- Author
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Kay Hofmann and Ju¨rg Tschopp
- Subjects
Programmed cell death ,Databases, Factual ,Unc ,Molecular Sequence Data ,Biophysics ,Apoptosis ,Biology ,Ankyrin ,Biochemistry ,Apo-1 ,Receptors, Tumor Necrosis Factor ,Death domain ,Structural Biology ,Cell Movement ,Genetics ,Animals ,Humans ,Amino Acid Sequence ,fas Receptor ,Receptor ,Molecular Biology ,Inhibitor of apoptosis domain ,Neuron guidance ,Binding Sites ,Base Sequence ,TNF receptor ,Retinoblastoma ,Cell Biology ,Fas ,Fas receptor ,Axons ,Cell biology ,Cancer research ,Reaper ,Signal transduction ,Sequence motif - Abstract
The interaction of Fas (Apo-1) and TNF receptor-1 with their respective ligands can lead to cell death. The so-called death domain, a sequence motif present in the cytoplasmic portion of the two receptors, has been identified as a critical structural element involved in signal transduction that leads to apoptosis. Here we describe several additional proteins which contain a death domain. Novel members of this family include proteins known to be implicated not only in apoptosis but also in neuron guidance.
- Published
- 1995
21. A region of the 75 kDa neurotrophin receptor homologous to the death domains of TNFR-I and Fas
- Author
-
Barbara Chapman
- Subjects
Receptors, Neuropeptide ,G protein ,Molecular Sequence Data ,Biophysics ,Molecular modeling ,Peptide ,Wasp Venoms ,Apoptosis ,NGF receptor ,Biology ,Biochemistry ,Receptor, Nerve Growth Factor ,Protein Structure, Secondary ,Receptors, Tumor Necrosis Factor ,Structural Biology ,Antigens, CD ,Genetics ,Animals ,Humans ,Amino Acid Sequence ,fas Receptor ,Alpha-helix ,Receptor ,Molecular Biology ,Death domain ,chemistry.chemical_classification ,Mastoparan ,Sequence Homology, Amino Acid ,Neurotrophin receptor ,Cell Biology ,Molecular biology ,Cell biology ,chemistry ,Receptors, Tumor Necrosis Factor, Type I ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Peptides ,Alpha helix ,Intracellular ,Neurotrophin - Abstract
Members of the NTR/TNFR family mediate apoptosis in many tissues, yet sequence homology has not been detected in their intracellular domains except for a ‘death domain’ in TNFR-I and Fas. Here, a region of the 75 kDa neurotrophin receptor (NTR) has been aligned with this apoptosis-inducing motif. Peptides at the carboxyl terminus of each domain potentially form amphiphilic helices, one of which (in NTR) resembles mastoparan, a G-protein activating peptide. Molecular models of three death-region peptides suggest that observed sequence similarities reflect a common structure, perhaps capable of undergoing an induced coil to helix transition.
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22. Solution structure of the isolated Pelle death domain
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Martin C. Moncrieffe, Katherine M. Stott, and Nicholas J. Gay
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Models, Molecular ,Magnetic Resonance Spectroscopy ,Pelle ,Protein Conformation ,Biophysics ,Crystallographic data ,Biology ,Protein Serine-Threonine Kinases ,Crystallography, X-Ray ,Biochemistry ,Protein Structure, Secondary ,Structural Biology ,Tube ,Genetics ,Animals ,Drosophila Proteins ,Protein kinase A ,Molecular Biology ,Death domain ,Cell Biology ,Solution structure ,NMR ,Cell biology ,Protein Structure, Tertiary ,Death domains ,Crystallography ,Drosophila ,Dimerization ,Ultracentrifugation - Abstract
The interaction between the death domains (DDs) of Tube and the protein kinase Pelle is an important component of the Toll pathway. Published crystallographic data suggests that the Pelle–Tube DD interface is plastic and implies that in addition to the two predominant Pelle–Tube interfaces, a third interaction is possible. We present the NMR solution structure of the isolated death domain of Pelle and a study of the interaction between the DDs of Pelle and Tube. Our data suggests the solution structure of the isolated Pelle DD is similar to that of Pelle DD in complex with Tube. Additionally, they suggest that the plasticity observed in the crystal structure may not be relevant in the functioning death domain complex.
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23. A protein related to a proteasomal subunit binds to the intracellular domain of the p55 TNF receptor upstream to its ‘death domain’
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Igor Mett, Mark Boldin, and David Wallach
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Programmed cell death ,DNA, Complementary ,Tumor necrosis factor ,Protein subunit ,Molecular Sequence Data ,Biophysics ,Apoptosis ,Sequence alignment ,Biology ,Biochemistry ,Receptors, Tumor Necrosis Factor ,Death domain ,Antigens, CD ,Structural Biology ,Genetics ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,Receptor ,Molecular Biology ,Peptide sequence ,Proteasome ,cDNA library ,Proteins ,Cell Biology ,TNF Receptor-Associated Factor 2 ,Molecular biology ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,Signaling ,Cell biology ,Receptors, Tumor Necrosis Factor, Type I ,Sequence Alignment ,Gene Deletion ,Two-hybrid system ,HeLa Cells - Abstract
A novel protein that binds specifically to the intracellular domain of the p55 tumor necrosis factor (TNF) receptor was cloned by two-hybrid screening of a HeLa cell cDNA library. Data bank searches revealed high sequence similarity of the protein (55.11) to yeast, nematode and plant proteins, whose functions are yet unknown. Significant similarity was also found between 55.11 and SEN3, the yeast equivalent of the p112 subunit of the 26S proteasome. Deletion analysis showed that the protein binds to the p55 receptor upstream to the region involved in induction of cell death.
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24. The RIP-like kinase, RIP3, induces apoptosis and NF-κB nuclear translocation and localizes to mitochondria
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Matthew V Lorenzi, Derong Liu, Gary M Kasof, Bruce Charles Gomes, and Judith Caroline Prosser
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Cell death ,Programmed cell death ,Tumor necrosis factor ,Molecular Sequence Data ,Biophysics ,Apoptosis ,Biochemistry ,Death domain ,Structural Biology ,Genetics ,Humans ,Amino Acid Sequence ,FADD ,Molecular Biology ,In Situ Hybridization, Fluorescence ,Caspase ,Cell Nucleus ,Chromosomes, Human, Pair 14 ,Inhibitor of apoptosis domain ,Sequence Homology, Amino Acid ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,NF-kappa B ,Cell Biology ,Blotting, Northern ,Fas receptor ,Chromosome 14q11.2 ,Caspase Inhibitors ,Molecular biology ,Mitochondria ,Protein Structure, Tertiary ,Cell biology ,Protein kinase domain ,Caspases ,Receptor-Interacting Protein Serine-Threonine Kinases ,biology.protein ,Protein Kinases ,HeLa Cells - Abstract
A RIP-like protein, RIP3, has recently been reported that contains an N-terminal kinase domain and a novel C-terminal domain that promotes apoptosis. These experiments further characterize RIP3-mediated apoptosis and NF-κB activation. Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system. The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia. RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-xL, dominant-negative FADD, as well as the general caspase inhibitor Z-VAD. Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2). However, caspase-1, -6, -8 and -9 inhibitors had little or no effect on RIP3-mediated apoptosis. Mutational analysis of RIP3 revealed that the C-terminus of RIP3 contributed to its apoptotic activity. This region is similar, but distinct, to the death domain found in many pro-apoptotic receptors and adapter proteins, including FAS, FADD, TNFR1, and RIP. Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity. RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis.
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25. Schizosaccharomyces pombe Rad9 contains a BH3-like region and interacts with the anti-apoptotic protein Bcl-2
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Kiyoshi Komatsu, Kevin M. Hopkins, Hong Gang Wang, and Howard B. Lieberman
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Programmed cell death ,Protein family ,Biophysics ,Gene Expression ,Cell Cycle Proteins ,Apoptosis ,Biology ,Biochemistry ,Cell Line ,Evolution, Molecular ,chemistry.chemical_compound ,Structural Biology ,Two-Hybrid System Techniques ,Rad9 ,Schizosaccharomyces ,Genetics ,Humans ,Bcl-2 ,Thiamine ,Genes, Suppressor ,Molecular Biology ,Conserved Sequence ,Death domain ,chemistry.chemical_classification ,Binding Sites ,Cell growth ,fungi ,Cell Biology ,biology.organism_classification ,Methyl Methanesulfonate ,Molecular biology ,Amino acid ,Methyl methanesulfonate ,Protein Structure, Tertiary ,Bcl-2 homology 3 domain ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,Schizosaccharomyces pombe ,DNA damage ,Cell Division ,Gene Deletion ,Mutagens ,Protein Binding - Abstract
Here we report that the Schizosaccharomyces pombe Rad9 (SpRad9) protein contains a group of amino acids with similarity to the Bcl-2 homology 3 death domain, which is required for SpRad9 interaction with human Bcl-2 and apoptosis induction in human cells. Overexpression of Bcl-2 in S. pombe inhibits cell growth independently of rad9, but enhances resistance of rad9-null cells to methyl methanesulfonate, ultraviolet and ionizing radiation. These observations suggest that SpRad9 may represent the first member of the Bcl-2 protein family identified in yeast, though the cell death pathways in S. pombe may differ from those found in mammals.
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26. Role of caspases in TNF-mediated regulation of cPLA2
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Martin Krönke and Sabine Adam-Klages
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Tumor necrosis factor ,Biophysics ,Down-Regulation ,Apoptosis ,Biochemistry ,Models, Biological ,Gene Expression Regulation, Enzymologic ,Phospholipases A ,Proinflammatory cytokine ,chemistry.chemical_compound ,Death domain ,Phospholipase A2 ,Structural Biology ,Cytosolic phospholipase A2 ,Genetics ,Animals ,Humans ,Phosphorylation ,Molecular Biology ,Caspase ,Inflammation ,biology ,Cell Death ,Tumor Necrosis Factor-alpha ,Hydrolysis ,Cell Biology ,Lipid signaling ,Cell biology ,Protein Structure, Tertiary ,Enzyme Activation ,chemistry ,Caspases ,biology.protein ,Arachidonic acid ,Tumor necrosis factor alpha ,Signal Transduction - Abstract
A major part of the proinflammatory activity of tumor necrosis factor (TNF) is brought about by cytosolic phospholipase A(2) (cPLA(2)) that generates arachidonic acid, the precursor for the production of leukotrienes and prostaglandins. The activation of cPLA(2) and induction of proinflammatory lipid mediators is in striking contrast to the teleologic meaning of apoptosis, which is to avoid an inflammatory reaction. In this review we highlight the evidence for a caspase-mediated cleavage and inactivation of cPLA(2), which seems to be an important mechanism by which TNF downregulates cPLA(2) activity in cells undergoing apoptosis.
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27. The putatively protective Onchocerca volvulus neuronal protein E1 is a member of the death domain protein family
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A. Domeyer, K.D. Erttmann, and M. Gallin
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Ankyrins ,Protein family ,Fas-Associated Death Domain Protein ,Molecular Sequence Data ,Biophysics ,Nerve Tissue Proteins ,Apoptosis ,Ankyrin ,Biochemistry ,Polymerase Chain Reaction ,Structural Biology ,Genetics ,Helminth ,Animals ,Humans ,FADD ,Amino Acid Sequence ,Caenorhabditis elegans ,Molecular Biology ,Conserved Sequence ,Filarioidea ,Death domain ,Adaptor Proteins, Signal Transducing ,chemistry.chemical_classification ,biology ,Sequence Homology, Amino Acid ,Calpain ,Cell Biology ,Exons ,Helminth Proteins ,biology.organism_classification ,Onchocerca volvulus ,Neuronal protein ,Recombinant Proteins ,Parasite ,chemistry ,biology.protein ,Sequence motif ,Carrier Proteins - Abstract
Here we show that E1, an ankyrin-related, potentially protective, neuronal protein of the human filarial nematode Onchocerca volvulus contains a death domain (DD), most similar to that of human Mort1/FADD (39% identity). In addition, sequence comparison of E1 to its homologue from Litomosoides sigmodontis and to Caenorhabditis elegans ankyrin defines two further putative functional domains. One represents the end of the spectrin-binding domain of ankyrins, the other an unique domain, most highly conserved between these nematodes, containing a calpain sequence motif. Thus, E1 may be involved in apoptosis, raising the possibility that protection against this parasitic helminth may be induced by apoptotic processes.
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28. Corrigendum to: The death domain protein p84N5, but not the short isoform p84N5s, is cell cycle-regulated and shuttles between the nucleus and the cytoplasm (FEBS 28723) [FEBS Letters 574 (2004) 13–19]
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Fabio Gasparri, Francesco Sola, Marta Muzio, and Giuseppe Locatelli
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Gene isoform ,Biophysics ,Cell Biology ,Cell cycle ,Biology ,Biochemistry ,Cell biology ,medicine.anatomical_structure ,Structural Biology ,Cytoplasm ,Genetics ,medicine ,Molecular Biology ,Nucleus ,Death domain - Full Text
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