27 results on '"Xin Lin"'
Search Results
2. Differential activity of mGlu7 allosteric modulators provides evidence for mGlu7/8 heterodimers at hippocampal Schaffer collateral-CA1 synapses.
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Xin Lin, Fisher, Nicole M., Dogra, Shalini, Senter, Rebecca K., Reed, Carson W., Kalbfleisch, Jacob J., Lindsley, Craig W., Asher, Wesley B., Zixiu Xiang, Niswender, Colleen M., and Javitch, Jonathan A.
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SYNAPSES , *NEURAL transmission , *EVOKED potentials (Electrophysiology) , *HOMODIMERS , *HIPPOCAMPUS (Brain) , *NEUROPLASTICITY , *HETERODIMERS - Abstract
Glutamate acts at eight metabotropic glutamate (mGlu) receptor subtypes expressed in a partially overlapping fashion in distinct brain circuits. Recent evidence indicates that specific mGlu receptor protomers can heterodimerize and that these heterodimers can exhibit different pharmacology when compared to their homodimeric counterparts. Group III mGlu agonist-induced suppression of evoked excitatory potentials and induction of long-term potentiation at Schaffer collateral-CA1 (SC-CA1) synapses in the rodent hippocampus can be blocked by the selective mGlu7 negative allosteric modulator (NAM), ADX71743. Curiously, a different mGlu7 NAM, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazo nolo[4,5-c]pyridin-4(5H)-one, failed to block these responses in brain slices despite its robust activity at mGlu7 homodimers in vitro. We hypothesized that this might result from heterodimerization of mGlu7 with another mGlu receptor protomer and focused on mGlu8 as a candidate given the reported effects of mGlu8-targeted compounds in the hippocampus. Here, we used complemented donor acceptor-resonance energy transfer to study mGlu7/8 heterodimer activation in vitro and observed that ADX71743 blocked responses of both mGlu7/7 homodimers and mGlu7/8 heterodimers, whereas 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one only antagonized responses of mGlu7/7 homodimers. Taken together with our electrophysiology observations, these results suggest that a receptor with pharmacology consistent with an mGlu7/8 heterodimer modulates the activity of SC-CA1 synapses. Building on this hypothesis, we identified two additional structurally related mGlu7 NAMs that also differ in their activity at mGlu7/8 heterodimers, in a manner consistent with their ability to inhibit synaptic transmission and plasticity at SC-CA1. Thus, we propose that mGlu7/8 heterodimers are a key molecular target for modulating the activity of hippocampal SC-CA1 synapses. [ABSTRACT FROM AUTHOR]
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- 2022
- Full Text
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3. RNA-binding protein RBM28 can translocate from the nucleolus to the nucleoplasm to inhibit the transcriptional activity of p53.
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Xin Lin, Liwen Zhou, Jianliang Zhong, Li Zhong, Ruhua Zhang, Tiebang Kang, and Yuanzhong Wu
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RNA-binding proteins , *NUCLEOLUS , *TUMOR suppressor proteins , *NUCLEOPROTEINS , *NUCLEOPLASM , *CANCER cell growth , *CANCER invasiveness - Abstract
RNA-binding protein RBM28 (RBM28), as a nucleolar component of spliceosomal small nuclear ribonucleoproteins, is involved in the nucleolar stress response. Whether and how RBM28 regulates tumor progression remains unclear. Here, we report that RBM28 is frequently overexpressed in various types of cancer and that its upregulation is associated with a poor prognosis. Functional and mechanistic assays revealed that RBM28 promotes the survival and growth of cancer cells by interacting with the DNA-binding domain of tumor suppressor p53 to inhibit p53 transcriptional activity. Upon treatment with chemotherapeutic drugs (e.g., adriamycin), RBM28 is trans-located from the nucleolus to the nucleoplasm, which is likely mediated via phosphorylation of RBM28 at Ser122 by DNA checkpoint kinases 1 and 2 (Chk1/2), indicating that RBM28 may act as a nucleolar stress sensor in response to DNA damage stress. Our findings not only reveal RBM28 as a potential biomarker and therapeutic target for cancers but also provide mechanistic insights into how cancer cells convert stress signals into a cellular response linking the nucleolus to regulation of the tumor suppressor p53. [ABSTRACT FROM AUTHOR]
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- 2022
- Full Text
- View/download PDF
4. Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and TGFβ-activated Kinase 1 (TAK1) Play Essential Roles in the C-type Lectin Receptor Signaling in Response to Candida albicans Infection
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Xin Lin, Bryant G. Darnay, and Sara Gorjestani
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Male ,Biology ,Biochemistry ,Proinflammatory cytokine ,Mice ,C-type lectin ,Candida albicans ,Animals ,Humans ,Lectins, C-Type ,Receptor ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,TNF Receptor-Associated Factor 6 ,Innate immune system ,MAP kinase kinase kinase ,Macrophages ,Candidiasis ,Pattern recognition receptor ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,MAP Kinase Kinase Kinases ,biology.organism_classification ,Cell biology ,Mice, Inbred C57BL ,Female ,Signal transduction ,Signal Transduction - Abstract
Tumor necrosis factor receptor-associated factor 6 (TRAF6) and TGFβ-activated kinase 1 (TAK1) are considered as key intermediates in Toll-like receptor (TLR) signaling. However, the role of TRAF6 and TAK1 in C-type lectin receptors (CLRs) in response to fungal infection has not been studied. In this study, we have utilized macrophages derived from TRAF6 knock-out mice and myeloid-specific TAK1-deficient mice and determined the role of TRAF6 and TAK1 in CLR-induced signal transduction events. We demonstrate that TRAF6 and TAK1 are required for NF-κB and JNK activation, and expression of proinflammatory cytokines in response to Candida albicans infection. Our results highlight TRAF6 and TAK1 as key components in the signaling cascade downstream of C-type lectin receptors and as critical mediators of the anti-fungal immune response. Therefore, our studies provide a mechanistic understanding of the host immune response to C. albicans, which has a significant impact for the development of anti-fungal therapeutics and in understanding risk-factors and determining susceptibility to C. albicans infection.
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- 2012
5. Disruption of the Integrin αLβ2 Transmembrane Domain Interface by β2 Thr-686 Mutation Activates αLβ2 and Promotes Micro-clustering of the αL Subunits
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Ardcharaporn Vararattanavech, Suet-Mien Tan, Xin Lin, and Jaume Torres
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biology ,Immunoprecipitation ,Cell adhesion molecule ,Chemistry ,Mutant ,Integrin ,Cell Biology ,Biochemistry ,Molecular biology ,Transmembrane domain ,Förster resonance energy transfer ,Ectodomain ,Cytoplasm ,Biophysics ,biology.protein ,Molecular Biology - Abstract
Integrins are type I heterodimeric cell adhesion molecules that mediate a wide array of biological processes. Integrin bidirectional signaling allows communication between the cell interior with its microenvironment. The integrin transmembrane domains (TMs) are the transducers of activation signal that is relayed from the cytoplasmic domains to the distal ligand binding site located in the ectodomain of the integrin and vice versa. In this study, we showed that the disruption of the αLβ2 TMs by mutation of a key interface residue Thr-686 in the β2 TM promoted αLβ2 activation with ICAMs binding properties that are reminiscent of an intermediate affinity receptor. The activated αLβ2 TM mutants, however, showed minimal reactivity with the reporter mAb KIM127 that recognizes a highly extended αLβ2. Two models of αLβ2 TM interaction were proposed previously. One with GXXXG-type interaction, and another that is based on TM cysteine-scanning analyses. Our data are consistent with a GXXXG-type interaction of the αLβ2 TMs. Finally, we observed by FRET analyses that perturbation of the αLβ2 TMs by β2 Thr-686 mutation facilitated αL micro-cluster formation. This was diminished by linking the αLβ2 TMs with a disulfide bond, which served to clasp the TMs. These data suggest that disruption of the TM interface changes αLβ2 ligand binding affinity, and it may contribute to αL micro-cluster formation.
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- 2009
6. Caveolin-1 Triggers T-cell Activation via CD26 in Association with CARMA1
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Xin Lin, Masahiko Uchiyama, Kei Ohnuma, Hirotoshi Tanaka, Kunika Nishibashi, Tadanori Yamochi, Osamu Hosono, Nam H. Dang, Nozomu Takahashi, Shinichiro Kina, and Chikao Morimoto
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Adenosine Deaminase ,Dipeptidyl Peptidase 4 ,T-Lymphocytes ,T cell ,Caveolin 1 ,Biology ,Lymphocyte Activation ,Biochemistry ,Jurkat cells ,Jurkat Cells ,medicine ,Humans ,Receptor ,Molecular Biology ,Lipid raft ,Glycoproteins ,CD86 ,TOLLIP ,Cell Biology ,Ligand (biochemistry) ,Cell biology ,CARD Signaling Adaptor Proteins ,medicine.anatomical_structure ,Guanylate Cyclase ,Apoptosis Regulatory Proteins ,Signal Transduction - Abstract
CD26 is a widely distributed 110-kDa cell surface glycoprotein with an important role in T-cell costimulation. We demonstrated previously that CD26 binds to caveolin-1 in antigen-presenting cells, and following exogenous CD26 stimulation, Tollip and IRAK-1 disengage from caveolin-1 in antigen-presenting cells. IRAK-1 is then subsequently phosphorylated to up-regulate CD86 expression, resulting in subsequent T-cell proliferation. However, it is unclear whether caveolin-1 is a costimulatory ligand for CD26 in T-cells. Using soluble caveolin-1-Fc fusion protein, we now show that caveolin-1 is the costimulatory ligand for CD26, and that ligation of CD26 by caveolin-1 induces T-cell proliferation and NF-kappaB activation in a T-cell receptor/CD3-dependent manner. We also demonstrated that the cytoplasmic tail of CD26 interacts with CARMA1 in T-cells, resulting in signaling events that lead to NF-kappaB activation. Ligation of CD26 by caveolin-1 recruits a complex consisting of CD26, CARMA1, Bcl10, and IkappaB kinase to lipid rafts. Taken together, our findings provide novel insights into the regulation of T-cell costimulation via the CD26 molecule.
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- 2007
7. Ubiquitination of RIP Is Required for Tumor Necrosis Factor α-induced NF-κB Activation
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Masayuki Kobayashi, Xin Lin, Yun You, Hongxiu Li, and Marzenna Blonska
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endocrine system ,Cell signaling ,endocrine system diseases ,Arginine ,Molecular Sequence Data ,Stimulation ,Protein Serine-Threonine Kinases ,medicine.disease_cause ,digestive system ,Biochemistry ,Jurkat Cells ,Ubiquitin ,medicine ,Humans ,Amino Acid Sequence ,Molecular Biology ,Tumor necrosis factor α ,Mutation ,Binding Sites ,biology ,Tumor Necrosis Factor-alpha ,Chemistry ,NF-kappa B ,nutritional and metabolic diseases ,Cell Biology ,Molecular biology ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,Cell biology ,Amino Acid Substitution ,Gene Expression Regulation ,Receptors, Tumor Necrosis Factor, Type I ,Receptor-Interacting Protein Serine-Threonine Kinases ,biology.protein ,Tumor necrosis factor alpha ,Nf κb activation ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
Stimulation of cells with tumor necrosis factor (TNFalpha) triggers a recruitment of various signaling molecules, such as RIP, to the TNFalpha receptor 1 complex, leading to activation of NF-kappaB. Previous studies indicate that RIP plays an essential role for TNFalpha-induced NF-kappaB activation, but the molecular mechanism by which RIP mediates TNFalpha signals to activate NF-kappaB is not fully defined. Earlier studies suggest that RIP undergoes a ligand-dependent ubiquitination. However, it remains to be determined whether the ubiquitination of RIP is required for TNFalpha-induced NF-kappaB activation. In this study, we have identified Lys377 of RIP as the functional ubiquitination site, because mutating this residue to arginine completely abolished RIP-mediated NF-kappaB activation. The K377R mutation of RIP cannot undergo ligand-dependent ubiquitination and fails to recruit its downstream signaling components into the TNFalpha receptor 1 complex. Together, our studies provide the first genetic evidence that the ubiquitination of RIP is required for TNFalpha-induced NF-kappaB activation.
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- 2006
8. Modulation of Werner Syndrome Protein Function by a Single Mutation in the Conserved RecQ Domain
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Jin-Shan Hu, Guang-Xin Lin, Robert M. Brosh, Jae Wan Lee, Kevin M. Doherty, Wen-Hsing Cheng, Cayetano von Kobbe, Wangyong Zeng, Rika Kusumoto, and Vilhelm A. Bohr
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Premature aging ,congenital, hereditary, and neonatal diseases and abnormalities ,Werner Syndrome Helicase ,DNA repair ,Amino Acid Motifs ,Molecular Sequence Data ,Mutation, Missense ,In Vitro Techniques ,Biology ,medicine.disease_cause ,Biochemistry ,Cell Line ,medicine ,Holliday junction ,Humans ,Amino Acid Sequence ,Nuclear Magnetic Resonance, Biomolecular ,Molecular Biology ,Conserved Sequence ,Werner syndrome ,Adenosine Triphosphatases ,Genetics ,Mutation ,Base Sequence ,RecQ Helicases ,Sequence Homology, Amino Acid ,Mutagenesis ,DNA Helicases ,DNA replication ,nutritional and metabolic diseases ,Helicase ,DNA ,Cell Biology ,medicine.disease ,Recombinant Proteins ,Protein Structure, Tertiary ,Exodeoxyribonucleases ,Mutagenesis, Site-Directed ,biology.protein ,Werner Syndrome - Abstract
Naturally occurring mutations in the human RECQ3 gene result in truncated Werner protein (WRN) and manifest as a rare premature aging disorder, Werner syndrome. Cellular and biochemical studies suggest a multifaceted role of WRN in DNA replication, DNA repair, recombination, and telomere maintenance. The RecQ C-terminal (RQC) domain of WRN was determined previously to be the major site of interaction for DNA and proteins. By using site-directed mutagenesis in the WRN RQC domain, we determined which amino acids might be playing a critical role in WRN function. A site-directed mutation at Lys-1016 significantly decreased WRN binding to fork or bubble DNA substrates. Moreover, the Lys-1016 mutation markedly reduced WRN helicase activity on fork, D-loop, and Holliday junction substrates in addition to reducing significantly the ability of WRN to stimulate FEN-1 incision activities. Thus, DNA binding mediated by the RQC domain is crucial for WRN helicase and its coordinated functions. Our nuclear magnetic resonance data on the three-dimensional structure of the wild-type RQC and Lys-1016 mutant proteins display a remarkable similarity in their structures.
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- 2005
9. Cloning of Human Stat5B
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Warren J. Leonard, Jian-Xin Lin, Susan D. John, William S. Modi, and Judy A. Mietz
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Interleukin 2 ,animal structures ,Janus kinase 1 ,T cell ,Janus kinase 3 ,food and beverages ,Cell Biology ,Biology ,Biochemistry ,Molecular biology ,medicine.anatomical_structure ,Complementary DNA ,medicine ,Receptor ,Cytokine receptor ,Molecular Biology ,Tyrosine kinase ,medicine.drug - Abstract
We have isolated a second human Stat5 cDNA, Stat5B, and demonstrated that the genes encoding both Stat5A and Stat5B are located at chromosome 17q11.2. Both genes were constitutively transcribed in peripheral blood lymphocytes. By using specific antisera, we demonstrated that both Stat5A and Stat5B are activated by interleukin-2 (IL-2) in peripheral blood lymphocytes, natural killer-like YT leukemia cells, and human T cell lymphotropic virus type I-transformed MT-2 T cells. In COS-7 cells, which constitutively express the Janus family tyrosine kinase Jak1, reconstitution of IL-2-induced Stat5A and Stat5B DNA binding activities was dependent on the coexpression of Jak3 along with the IL-2 receptor beta chain and the common cytokine receptor gamma-chain. This IL-2-induced Stat5 activation was dependent on the presence of either of two tyrosines (Tyr-392 or Tyr-510) in the IL-2 receptor beta chain, indicating that either of these two tyrosines can serve as a docking site. Moreover, we demonstrated that human Stat5 activation is also dependent on Tyr-694 in Stat5A and Tyr-699 in Stat5B, indicating that these tyrosines are required for dimerization. The COS-7 reconstitution system described herein provides a valuable assay for further elucidation of the IL-2-activated JAK-STAT pathway.
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- 1996
10. Biosynthesis of the Sesquiterpene Antibiotic Albaflavenone in Streptomyces coelicolor A3(2).
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Bin Zhao, Xin Lin, Li Lei, Lamb, David C., Kelly, Steven L., Waterman, Michael R., and Canes, David E.
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SESQUITERPENES , *ANTIBIOTICS , *STREPTOMYCES , *CYTOCHROME P-450 , *HYDROCARBONS - Abstract
Cytochrome P450 170A1 (CYP170A1) is encoded by the sco5223 gene of the Gram-positive, soil-dwelling bacterium Streptomyces coelicolor A3(2) as part of a two-gene cluster with the sco5222 gene. The SCO5222 protein is a sesquiterpene synthase that catalyzes the cyclization of farnesyl diphosphate to the novel tricyclic hydrocarbon, epi-isozizaene (Lin, X., Hopson, R., and Cane, D. E. (2006) J. Am. Chem. Soc. 128, 6022- 6023). The presence of CYP170A1 (sco5223) suggested that epiisozizaene might be further oxidized by the transcriptionally coupled P450. We have now established that purified CYP170A1 carries out two sequential allylic oxidations to convert epi-isozizaene to an epimeric mixture of albaflavenols and thence to the sesquiterpene antibiotic albaflavenone. Gas chromatography/mass spectrometry analysis of S. coelicolor culture extracts established the presence of albaflavenone in the wild-type strain, along with its precursors epi-isozizaene and the albaflavenols. Disruption of the CYP170A1 gene abolished bio-synthesis of both albaflavenone and the albaflavenols, but not epi-isozizaene. The combined results establish for the first time the presence of albaflavenone in S. coelicolor and clearly demonstrate that the biosynthesis of this antibiotic involves the coupled action of epi-isozizaene synthase and CYP170A1. [ABSTRACT FROM AUTHOR]
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- 2008
- Full Text
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11. Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17.
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Liu, Xikui K., Xin Lin, and Gaffen, Sarah L.
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INTERLEUKINS , *GENETIC transcription , *T cells , *CYCLOSPORINE , *GENE expression , *BINDING sites - Abstract
The biological activities of the inflammatory cytokine interleukin (IL)-17 have been widely studied. However, comparatively little is known about how IL-17 expression is controlled. Here, we examined the basis for transcriptional regulation of the human IL-17 gene. IL-17 secretion was induced in peripheral blood mononuclear cells following anti-CD3 cross-linking to activate the T cell receptor (TCR), and costimulatory signaling through CD28 strongly enhanced CD3-induced IL-17 production. To define cis-acting elements important for IL-17 gene regulation, we cloned 1.25 kb of genomic sequence upstream of the transcriptional start site. This putative prorooter was active in Jurkat T cells following CD3 and CD28 cross-linking, and its activity was inhibited by cyclosporin A and MAPK inhibitors. The promoter was also active in Hut102 T cells, which we have shown to secrete IL-17 constitutively. Overexpression of nuclear factor of activated T cells (NFAT) or Ras enhanced IL-17 promoter activity, and studies in Jurkat lines deficient in specific TCR signaling pathways provided supporting evidence for a role for NFAT. To delineate the IL-17 minimal prorooter, we created a series of 5' truncations and identified a region between -232 and -159 that was sufficient for inducible promoter activity. Interestingly, two NFAT sites were located within this region, which bound to NFATc1 and NFATc2 in nuclear extracts from Hut102 and Jurkat cells. Moreover, mutations of these sites dramatically reduced both specific DNA binding and reporter gene activity, and chromatin immunoprecipitation assays showed occupancy of NFAT at this region in vivo. Together, these data show that NFAT is the crucial sensor of TCR signaling in the IL-17 promoter. [ABSTRACT FROM AUTHOR]
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- 2004
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12. Tumor necrosis factor and interleukin-1 cause a rapid and transient stimulation of c-fos and c-myc mRNA levels in human fibroblasts
- Author
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Jan Vilcek and Jian-Xin Lin
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biology ,medicine.medical_treatment ,Interleukin ,Stimulation ,Cell Biology ,Cycloheximide ,Biochemistry ,c-Fos ,Molecular biology ,chemistry.chemical_compound ,medicine.anatomical_structure ,Cytokine ,chemistry ,biology.protein ,medicine ,Tumor necrosis factor alpha ,Fibroblast ,Molecular Biology ,Fetal bovine serum - Abstract
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) were shown previously to be mitogenic for human fibroblasts. Here we show that recombinant human TNF and recombinant human IL-1 alpha increase steady state levels of c-fos and c-myc proto-oncogene mRNAs in quiescent human FS-4 fibroblasts. Proto-oncogene mRNA levels were enhanced within 20 min of TNF or IL-1 addition, peaked at 30 min, and declined to undetectable levels (c-fos) or basal levels (c-myc) by 60 or 90 min. A similar rapid increase in c-fos and c-myc mRNA was seen in quiescent FS-4 cells exposed to cycloheximide. However, in the presence of cycloheximide, both proto-oncogene mRNA levels continued to rise for at least 90 min. The transient nature of the increase in c-myc mRNA levels appears to be a response characteristic for TNF and IL-1 because in quiescent FS-4 cells exposed to 10% fetal bovine serum, steady state levels of c-myc mRNA remained elevated for at least 4 h.
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- 1987
13. Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and TGFβ-activated Kinase 1 (TAK1) Play Essential Roles in the C-type Lectin Receptor Signaling in Response to Candida albicans Infection.
- Author
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Gorjestani, Sara, Darnay, Bryant G., and Xin Lin
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TUMOR necrosis factor receptors , *PROTEIN kinases , *LECTINS , *CANDIDA albicans , *MYCOSES , *BIOCHEMISTRY - Abstract
Tumor necrosis factor receptor-associated factor 6 (TRAF6) and TGFβ-activated kinase 1 (TAK1) are considered as key intermediates in Toll-like receptor (TLR) signaling. However, the role of TRAF6 and TAK1 in C-type lectin receptors (CLRs) in response to fungal infection has not been studied. In this study, we have utilized macrophages derived from TRAF6 knock-out mice and myeloid-specific TAK1-deficient mice and determined the role of TRAF6 and TAK1 in CLR-induced signal transduction events. We demonstrate that TRAF6 and TAK1 are required for NF-κB and JNK activation, and expression of proinflammatory cytokines in response to Candida albicans infection. Our results highlight TRAF6 and TAK1 as key components in the signaling cascade downstream of C-type lectin receptors and as critical mediators of the anti-fungal immune response. Therefore, our studies provide a mechanistic understanding of the host immune response to C. albicans, which has a significant impact for the development of anti-fungal therapeutics and in understanding risk-factors and determining susceptibility to C. albicans infection. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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14. The Small Hydrophobic Protein of the Human Respiratory Syncytial Virus Forms Pentameric Ion Channels.
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Siok-Wan Gan, Tan, Edward, Xin Lin, Dejie Yu, Juejin Wang, Tan, Gregory Ming-Yeong, Vararattanavech, Ardcharaporn, Chiew Ying Yeo, Cin Huang Soon, Tuck Wah Soong, Pervushin, Konstantin, and Torres, Jaume
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RESPIRATORY syncytial virus , *ION channels , *PROTEIN structure , *MICELLES , *CELL membranes , *LIPIDS - Abstract
The small hydrophobic (SH) protein is encoded by the human respiratory syncytial virus. Its absence leads to viral attenuation in the context of whole organisms, and it prevents apoptosis in infected cells. Herein, we have examined the structure of SH protein in detergent micelles and in lipid bilayers, by solution NMR and attenuated total reflection-Fourier transform infrared spectroscopy, respectively. We found that SH protein has a single α-helical transmembrane domain and forms homopentamers in several detergents. In detergent micelles, the transmembrane domain is flanked N-terminally by an α-helix that forms a ring around the lumen of the pore and C-terminally by an extended β-turn. SH protein was found in the plasma membrane of transiently expressing HEK 293 cells, which showed pH-dependent (acid-activated) channel activity. Channel activity was abolished in mutants lacking both native His residues, His22 and His51, but not when either His was present. Herein, we propose that the pentameric model of SH protein presented is a physiologically relevant conformation, albeit probably not the only one, in which SH contributes to RSV infection and replication. Viroporins are short (∼100 amino acids) viral membrane proteins that form oligomers of a defined size, act as proton or ion channels, and in general enhance membrane permeability in the host. However, with some exceptions, their precise biological role of their channel activity is not understood. In general, viroporins resemble poorly specialized proteins but are nevertheless critical for viral fitness. In vivo, viruses lacking viroporins usually exhibit an attenuated or weakened phenotype, altered tropism, and diminished pathological effects. We have chosen to study the SH protein, 64 amino acids long, found in the human respiratory syncytial virus because of the effect of RSV on human health and the lack of adequate antivirals. We show that SH protein forms oligomers that behave as ion channels when activated at low pH. This study adds SH protein to a growing group of viroporins that have been structurally characterized. Although the precise biological role of this pentameric channel is still unknown, this report is nevertheless essential to fill some of the many gaps that exist in the understanding of SH protein function. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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15. Linear ubiquitination of cFLIP induced by LUBAC contributes to TNFα-induced apoptosis.
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Yong Tang, Donghyun Joo, Guangna Liu, Hailin Tu, Jeffrey You, Jianping Jin, Xueqiang Zhao, Mien-Chie Hung, and Xin Lin
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UBIQUITINATION , *TUMOR necrosis factors , *APOPTOSIS , *PROTEASOMES , *BIODEGRADATION - Abstract
The linear ubiquitin chain assembly complex (LUBAC) regulates NF-κB activation by modifying proteins with linear (M1- linked) ubiquitination chains. Although LUBAC also regulates the apoptosis pathway, the precise mechanism by whichLUBAC regulates apoptosis remains not fully defined. Here, we report that LUBAC-mediated M1-linked ubiquitination of cellular FLICE-like inhibitory protein (cFLIP), an anti-apoptotic molecule, contributes to tumor necrosis factor (TNF)β-induced apoptosis. Wefound that deficiency of RNF31, the catalytic subunit of the LUBAC complex, promoted cFLIP degradation in a proteasome-dependent manner. Moreover, we observed RNF31 directly interact with cFLIP, and LUBAC further conjugated M1-linked ubiquitination chains at Lys-351 and Lys-353 of cFLIP to stabilize cFLIP, thereby protecting cells from TNFβ- induced apoptosis. Together, our study identifies a new substrate of LUBAC and reveals a new molecular mechanism through which LUBAC regulates TNFβ-induced apoptosis via M1-linked ubiquitination. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
16. C-type Lectin Receptor Dectin-3 Mediates Trehalose 6,6'-Dimycolate (TDM)-induced Mincle Expression through CARD9/Bcl10/MALT1-dependent Nuclear Factor (NF)-κB Activation.
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Xue-Qiang Zhao, Le-Le Zhu, Qing Chang, Changying Jiang, Yun You, Tianming Luo, Xin-Ming Jia, and Xin Lin
- Subjects
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GLUCANS , *TREHALOSE , *NF-kappa B , *IMMUNITY , *IMMUNOLOGY - Abstract
Previous studies indicate that both Dectin-3 (also called MCL or Clec4d) and Mincle (also called Clec4e), two C-type lectin receptors, can recognize trehalose 6,6'-dimycolate (TDM), a cell wall component from mycobacteria, and induce potent innate immune responses. Interestingly, stimulation of Dectin-3 by TDM can also induce Mincle expression, which may enhance the host innate immune system to sense Mycobacterium infection. However, the mechanism by which Dectin-3 induces Mincle expression is not fully defined. Here, we show thatTDMinduced Mincle expression is dependent on Dectin-3-mediated NF-κB, but not nuclear factor of activated T-cells (NFAT), activation, and Dectin-3 induces NF-κB activation through the CARD9-BCL10-MALT1 complex. We found that bone marrowderived macrophages from Dectin-3-deficient mice were severely defective in the induction of Mincle expression in response to TDM stimulation. This defect is correlated with the failure of TDM-induced NF-κB activation in Dectin-3-deficient bone marrow-derived macrophages. Consistently, inhibition of NF-κB, but not NFAT, impaired TDM-induced Mincle expression, whereas NF-κB, but not NFAT, binds to the Mincle promoter. Dectin-3-mediated NF-κB activation is dependent on the CARD9-Bcl10-MALT1 complex. Finally, mice deficient for Dectin-3 or CARD9 produced much less proinflammatory cytokines and keyhole limpet hemocyanin (KLH)-specific antibodies after immunization with an adjuvant containingTDM.Overall, this study provides the mechanism by which Dectin-3 induces Mincle expression in response to Mycobacterium infection, which will have significant impact to improve adjuvant and design vaccine for antimicrobial infection. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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17. Differential Regulation of c-Jun Protein Plays an Instrumental Role in Chemoresistance of Cancer Cells.
- Author
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Yan Xia, Weiwei Yang, Wen Bu, Haitao Ji, Xueqiang Zhao, Yanhua Zheng, Xin Lin, Yi Li, and Zhimin Lu
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C-Jun N-terminal kinases , *CANCER cells , *CISPLATIN , *CANCER treatment , *DRUG resistance , *MAMMARY gland tumors - Abstract
The chemotherapeutic drug cisplatin (cis-diamminedichloroplatinum( II) (CDDP)) is widely used in the treatment of human cancers. However, the mechanism underlying intrinsic tumor resistance to CDDP remains elusive. Here, we demonstrate that treatment with CDDP resulted in down-regulation of c-Jun expression via caspase-9-dependent cleavage of c-Jun at Asp-65 and MEKK1-mediated ubiquitylation and degradation of c-Jun in CDDP-sensitive cancer cells. In contrast, activation of JNK2 (but not JNK1) phosphorylated and up-regulated the expression of c-Jun in CDDP-resistant cells. Activated c-Jun bound to the promoter regions of the MDR1 gene and promoted the expression of MDR1. Expression of a cleavage-resistant c-Jun mutant (D65A) suppressed CDDP-induced apoptosis of CDDP-sensitive cells, whereas depletion of JNK2, c-Jun, or MDR1 in CDDPresistant cancer cells promoted apoptosis upon CDDP treatment. In addition, mammary gland tumors induced by polyomavirus middle T antigen in JNK2-/- mice were more sensitive toCDDPcompared with those in JNK2+/+ mice. These findings highlight the instrumental role of c-Jun in the resistance of tumors to treatment withCDDPand indicate that c-Jun is a molecular target for improving cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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18. Phospholipase Cγ2 (PLCγ2) Is Key Component in Dectin-2 Signaling Pathway, Mediating Anti-fungal Innate Immune Responses.
- Author
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Gorjestani, Sara, Mei Yu, Tang, Bing, Dekai Zhang, Demin Wang, and Xin Lin
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LECTINS , *PHOSPHOLIPASES , *MYCOSES , *CANDIDA albicans , *REACTIVE oxygen species , *LABORATORY mice - Abstract
C-type lectin receptors (CLRs) such as Dectin-2 function as pattern recognition receptors to sense fungal infection. However, the signaling pathways induced by these receptors remain largely unknown. Previous studies suggest that the CLR-induced signaling pathway may utilize similar signaling components as the B cell receptor-induced signaling pathway. Phospholipase Cγ2 (PLCγ2) is a key component in B cell receptor signaling, but its role in other signaling pathways has not been fully characterized. Here, we show that PLCγ2 functions down- stream of Dectin-2 in response to the stimulation by the hyphal form of Candida albi cans, an opportunistic pathogenic fungus. Using PLCγ2- and PLCγ1-deficient macrophages, we found that the lack of PLCγ2, but not PLCγ1, impairs cytokine production in response to infection with C. albi cans. PLCγ2 deficiency results in the defective activation of NF-icB and MAPK and a significantly reduced production of reactive oxygen species following fungal challenge. In addition, PLCγ2-deficient mice are defective in clearing C. albicans infection in vivo. Together, these findings demonstrate that PLCγ2 plays a critical role in CLR-induced signaling pathways, governing antifungal innate immune responses. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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19. Crystal Structure of Albaflavenone Monooxygenase Containing a Moonlighting Terpene Synthase Active Site.
- Author
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Bin Zhao, Li Lei, VassyIyev, Dmitry G., Xin Lin, Cane, David E., Kelly, Steven L., Hang Yuan, Lamb, David C., and Waterman, Michael R.
- Subjects
- *
MONOOXYGENASES , *TERPENES , *BINDING sites , *MOLECULAR structure , *STREPTOMYCES coelicolor , *MUTAGENESIS , *CYTOCHROMES - Abstract
Albaflavenone synthase (CYP17OA1) is a monooxygenase catalyzing the final two steps in the biosynthesis of this antibiotic in the soil bacterium, Streptornyces coelicolor A3(2). Interestingly, CYP17OA1 shows no stereo selection forming equal amounts of two albaflavenol epimers, each of which is oxidized in turn to albaflavenone. To explore the structural basis of the reaction mechanism, we have studied the crystal structures of both ligand- free CYP17OA1 (2.6 Å) and complex of endogenous substrate (epiisozizaene) with CYP170A1 (3.3 Å). The structure of the complex suggests that the proximal episozizaene molecules may bind to the heme iron in two orientations. In addition, much to our surprise, we have found that albaflavenone synthase also has a second, completely distinct catalytic activity corresponding to the synthesis of farnesene isomers from farnesyl diphosphate. Within the cytochrome P450 a-helical domain both the primary sequence and x-ray structure indicate the presence of a novel terpene synthase active site that is moonlighting on the P450 structure. This includes signature sequences for divalent cation binding and an a-helical barrel. This barrel is unusual because it consists of only four helices rather than six found in all other terpene synthases. Mutagenesis establishes that this barrel is essential for the terpene synthase activity of CYP17OA1 but not for the monooxygenase activity. This is the first bifunctional P450 discovered to have another active site moonlighting on it and the first time a terpene synthase active site is found moonlighting on another protein. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
20. NF-κB Transcription Factor p50 Critically Regulates Tissue Factor in Deep Vein Thrombosis.
- Author
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Yi-Dan Li, Bu-Qing Ye, Sheng-Xi Zheng, Jin-Tao Wang, Jian-Guo Wang, Ming Chen, Ji-Guo Liu, Xin Hui Pei, Li-Jing Wang, Zhi-Xin Lin, Gupta, Kalpna, Mackman, Nigel, Slungaard, Arne, Key, Nigel S., and Jian-Guo Geng
- Subjects
- *
TRANSCRIPTION factors , *PROTEIN S deficiency , *THROMBOSIS , *DEFICIENCY diseases , *BLOOD coagulation - Abstract
NF-κB transcription factors regulate the expression of tissue factor (TF), a principal initiator of the coagulation cascade. Dominant among them is the p50/p65 heterodimer. Here we report that Andrographolide (Andro; a p50 inhibitor) and genetic deletion of p50 attenuated TF activity in stimulated endothelial cells and monocytes/macrophages. Results of the electrophoretic mobility "supershift" assay and chromatin immunoprecipitation demonstrated the direct interaction of the p50/p65 heterodimer with the NF-κB site of the human TF promoter. Andro-treated and p50 null mice both exhibited blunted TF expression and reduced venous thrombosis, which were recapitulated by an anti-murine TF antibody in vivo. Our findings thus indicate that regulation of TF by NF-κB transcription factor p50 is essential for the pathogenesis of deep vein thrombosis and suggest that specific inhibitors of p50, such as Andro, may be therapeutically valuable for preventing and perhaps treating venous thrombosis. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
21. CARMA1 Coiled-coil Domain Is Involved in the Oligomerization and Subcellular Localization of CARMA1 and Is Required for T Cell Receptor-induced NF-κB Activation.
- Author
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Tanner, Matthew J., Hanel, Walter, Gaffen, Sarah L., and Xin Lin
- Subjects
- *
T cell receptors , *CELL membranes , *LYMPHOCYTES , *CELL receptors , *MICROBIAL genetics , *BACTERIOPHAGES , *T cells - Abstract
T lymphocyte (T cell) activation and proliferation is induced by the activation of multiple signal transduction pathways. Earlier studies indicate that CARMA1, a Caspase Recruitment Domain (CARD) and Membrane-associated GUanylate Kinase domain (MAGUK)-containing scaffold protein, plays an essential role in NF-κB activation induced by the costimulation of T cell receptor (TCR) and CD28 molecules. However, the molecular mechanism by which CARMA1 mediates TCR-CD28 costimulation-induced NF-κB activation is not fully understood. Here we show that CARMA1 is constitutively oligomerized. This oligomerization of CARMA1 is through its Coiled-coil domain. Disruption of the predicted structure of the Coiled-coil domain of CARMA1 impaired its oligomerization and, importantly, abrogated CARMA1-mediated NF-κB activation. Interestingly, disruption of the CC1 domain abrogates CARMA1 localization, whereas disruption of the CC2 domain seems to inhibit CARMA1 self-association. Together, our results demonstrate that the oligomerization of CARMA1 is required for TCR-induced NF-κB activation. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
22. Caveolin-1 Triggers T-cell Activation via CD26 in Association with CARMA1.
- Author
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Ohnuma, Kei, Uchiyama, Masahiko, Yamochi, Tadanori, Nishibashi, Kunika, Hosono, Osamu, Takahashi, Nozomu, Kina, Shinichiro, Tanaka, Hirotoshi, Xin Lin, Dang, Nam H., and Morimoto, Chikao
- Subjects
- *
T-cell receptor genes , *GLYCOPROTEINS , *GLYCOCONJUGATES , *GLYCOPROTEIN hormones , *CHORIONIC gonadotropins , *CELL membranes , *CELL growth - Abstract
CD26 is a widely distributed 110-kDa cell surface glycoprotein with an important role in T-cell costimulation. We demonstrated previously that CD26 binds to caveolin-1 in antigen-presenting cells, and following exogenous CD26 stimulation, Tollip and IRAK-1 disengage from caveolin-1 in antigen-presenting cells. IRAK-1 is then subsequently phosphorylated to up-regulate CD86 expression, resulting in subsequent T-cell proliferation. However, it is unclear whether caveolin-1 is a costimulatory ligand for CD26 in T-cells. Using soluble caveolin-1-Fc fusion protein, we now show that caveolin-1 is the costimulatory ligand for CD26, and that ligation of CD26 by caveolin-1 induces T-cell proliferation and NF-κB activation in a T-cell receptor/CD3-dependent manner. We also demonstrated that the cytoplasmic tail of CD26 interacts with CARMA1 in T-cells, resulting in signaling events that lead to NF-κB activation. Ligation of CD26 by caveolin-1 recruits a complex consisting of CD26, CARMA1, Bcl10, and IKB kinase to lipid rafts. Taken together, our findings provide novel insights into the regulation of T-cell costimulation via the CD26 molecule. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
23. Indirubin Enhances Tumor Necrosis Factor-induced Apoptosis through Modulation of Nuclear Factor-κB Signaling Pathway.
- Author
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Sethi, Gautam, Kwang Seok Ahn, Sandur, Santosh K., Xin Lin, Chaturvedi, Madan M., and Aggarwal, Bharat B.
- Subjects
- *
TUMOR necrosis factors , *CYTOKINES , *GLYCOPROTEINS , *NF-kappa B , *DNA-binding proteins , *TRANSCRIPTION factors - Abstract
Although indirubin is known to exhibit anti-cancer and anti-inflammatory activities, very little is known about its mechanism of action. In this study, we investigated whether indirubin mediates its effects through interference with the NF-κB pathway. As examined by the DNA binding of NF-κB, we found that indirubin suppressed tumor necrosis factor (TNF)-induced NP-κB activation in a dose- and time-dependent manner. Indirubin also suppressed the NP-κB activation induced by various inflammatory agents and carcinogens. Further studies showed that indirubin blocked the phosphorylation and degradation of IκBα through the inhibition of activation of IκBα kinase and phosphorylation and nuclear translocation of p65. NF-κB reporter activity induced by TNFR1, TNF receptor-associated death domain, TRAF2, TAK1, NP-κB-inducing kinase, and IKKβ was inhibited by indirubin but not that induced by p65 transfection. We also found that indirubin inhibited the expression of NP-κB-regulated gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl-xL, and TRAF1), proliferation (cyclin D1 and c-Myc), and invasion (COX-2 and MMP-9). This correlated with enhancement of the apoptosis induced by TNF and the chemotherapeutic agent taxol in human leukemic KBM-5 cells. Indirubin also suppressed cytokine-induced cellular invasion. Overall, our results indicate that anti-cancer and anti-inflammatory activities previously assigned to indirubin may be mediated in part through the suppression of the NP-κB activation pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
24. Ubiquitination of RIP Is Required for Tumor Necrosis Factor α-induced NF-κB Activation.
- Author
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Hongxiu Li, Kobayashi, Masayuki, Blonska, Marzenna, Yun You, and Xin Lin
- Subjects
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TUMOR necrosis factors , *CYTOKINES , *GROWTH factors , *AMINO acids , *PROTEINS , *CELLS - Abstract
Stimulation of cells with tumor necrosis factor (TNFα) triggers a recruitment of various signaling molecules, such as RIP, to the TNFα receptor 1 complex, leading to activation of NF-κB. Previous studies indicate that RIP plays an essential role for TNFα-induced NF-βB activation, but the molecular mechanism by which RIP mediates TNFα signals to activate NF-κB is not fully defined. Earlier studies suggest that RIP undergoes a ligand-dependent ubiquitination. However, it remains to be determined whether the ubiquitination of RIP is required for TNFα-induced NF-βB activation. In this study, we have identified Lys377 of RIP as the functional ubiquitination site, because mutating this residue to arginine completely abolished RIP-mediated NF-κB activation. The K377R mutation of RIP cannot undergo ligand-dependent ubiquitination and fails to recruit its downstream signaling components into the TNFα receptor 1 complex. Together, our studies provide the first genetic evidence that the ubiquitination of RIP is required for TNFα-induced NF-κB activation. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
25. TAK1 Is Recruited to the Tumor Necrosis Factor-α (TN F-α) Receptor 1 Complex in a Receptor-interacting Protein (RIP)- dependent Manner and Cooperates with MEKK3 Leading to NF-κB Activation.
- Author
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Blonska, Marzenna, Shambharkar, Prashant B., Kobayashi, Masayuki, Dongyu Zhang, Sakurai, Hiroaki, Bing Su, and Xin Lin
- Subjects
- *
PROTEINS , *TUMOR necrosis factors , *NF-kappa B , *DNA-binding proteins , *TRANSCRIPTION factors , *ORGANIC compounds - Abstract
Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor-α (TNF-α)-induced IκB kinase (IKK) activation and subsequent activation of transcription factor NF-κB. However, the molecular mechanism by which RIP mediates TNF-α-induced NF-κB activation is not completely defined. In this study, we have found that TAK1 is recruited to the TNF-α receptor complex in a RIP-dependent manner following the stimulation of TNF-α receptor 1 (TNF-R1). Moreover, a forced recruitment of TAK 1 to TNF-R1 in the absence of RIP is sufficient to mediate TNF-α-induced NF-κB activation, indicating that the major function of RIP is to recruit its downstream kinases to the TNF-R1 complex. Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3. The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activity of TAK1. Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1, TAB1 is required for TAK1 activation and subsequent MEKK3 phosphorylation. Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-κB in TNF-α signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
26. Modulation of Werner Syndrome Protein Function by a Single Mutation in the Conserved RecQ Domain.
- Author
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Jae Wan Lee, Kusumoto, Rika, Doherty, Kevin M., Guang-Xin Lin, Wangyong Zeng, Wen-Hsing Cheng, Von Kobbe, Cayetano, Brosh Jr., Robert M., Jin-Shan Hu, and Bohr, Vilhelm A.
- Subjects
- *
WERNER'S syndrome , *GENES , *DNA , *PROTEINS , *AGING , *DEVELOPMENTAL biology - Abstract
Naturally occurring mutations in the human RECQ3 gene result in truncated Werner protein (WRN) and manifest as a rare premature aging disorder, Werner syndrome. Cellular and biochemical studies suggest a multifaceted role of WRN in DNA replication, DNA repair, recombination, and telomere maintenance. The RecQ C-terminal (RQC) domain of WRN was determined previously to be the major site of interaction for DNA and proteins. By using site-directed mutagenesis in the WRN RQC domain, we determined which amino acids might be playing a critical role in WRN function. A site-directed mutation at Lys-1016 significantly decreased WRN binding to fork or bubble DNA substrates. Moreover, the Lys-1016 mutation markedly reduced WRN helicase activity on fork, D-loop, and Holliday junction substrates in addition to reducing significantly the ability of WRN to stimulate FEN-1 incision activities. Thus, DNA binding mediated by the RQC domain is crucial for WRN helicase and its coordinated functions. Our nuclear magnetic resonance data on the three-dimensional structure of the wild-type RQC and Lys-1016 mutant proteins display a remarkable similarity in their structures. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
27. MALT1/Paracaspase Is a Signaling Component Downstream of CARMA1 and Mediates T Cell Receptor-induced NF-κB Activation.
- Author
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Tuanjie Che, Igor C., Yun You, Donghai Wang, Tanner, Matthew J., Dixit, Vishva M., and Xin Lin
- Subjects
- *
T cell receptors , *TRANSCRIPTION factors , *BINDING sites , *CELLULAR signal transduction , *PROTEINS , *IMMUNE response - Abstract
T cell receptor (TCR) induces a series of signaling cascades and leads to activation of multiple transcription factors, including NF-κB. Although the mechanism of TCR-induced NF-κB activation is not fully understood, recent studies indicate that Bcl10 and CARMA1, two adaptor/scaffold proteins, play essential roles in mediating TCR-induced NF-κB activation. MALT1/paracaspase is a caspase-like protein that contains an Nterminal death domain, two Ig-like domains, and a C-terminal caspase-like domain. It binds to Bcl10 through its Ig-like domains and cooperates with Bcl10 to activate NF-κB. Recently, it has been shown that MALT1 is involved in mediating TCR signal transduction, leading to activation of NF-κB. In this study, we show that MALT1 is recruited into the lipid rafts of the immunological synapse following activation of the TCR and the CD28 coreceptor (CD3/CD28 costimulation). This recruitment of MALT1 is dependent on CARMA1 because CD3/CD28 costimulation failed to recruit MALT1 into lipid rafts in CARMA1-deficient T cells. In addition, we also found that MALT1 not only binds to Bcl10 directly, but also associates with CARMA1 in a Bcl10-independent manner. Therefore, MALT1, Bcl10, and CARMA1 form a trimolecular complex. Expression of a MALT1 deletion mutant containing only the N-terminal death domain and the two Ig-like domains completely blocked CD3/CD28 costimulation-induced, but not tumor necrosis factor-α-induced, NF-κB activation. Together, these results indicate that MALT1 is a crucial signaling component in the TCR signaling pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
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