The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
David S Bredt - One of the best experts on this subject based on the ideXlab platform.
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transmembrane ampa receptor Regulatory Proteins and cornichon 2 allosterically regulate ampa receptor antagonists and potentiators
Journal of Biological Chemistry, 2011Co-Authors: Douglas A Schober, Douglas Linn Gernert, Matthew W Jeffries, Martin B. Gill, Akihiko Kato, Christian C Felder, Paul L. Ornstein, Hong Yu, David S BredtAbstract:Abstract AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor Regulatory Proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits. Here, we asked whether AMPA receptor modulatory subunits might resolve this discrepancy. We find that the cerebellar TARP, stargazin (γ-2), enhances the binding affinity of the AMPA receptor potentiator [3H]-LY450295 and confers sensitivity to displacement by non-competitive antagonists. In cerebellar membranes from stargazer mice, [3H]-LY450295 binding is reduced and relatively resistant to displacement by non-competitive antagonists. Coexpression of AMPA receptors with CNIH-2, which is expressed in the hippocampus and at low levels in the cerebellar Purkinje neurons, confers partial sensitivity of [3H]-LY450295 potentiator binding to displacement by non-competitive antagonists. Autoradiography of [3H]-LY450295 binding to stargazer and γ-8-deficient mouse brain sections, demonstrates that TARPs regulate the pharmacology of allosteric AMPA potentiators and antagonists in the cerebellum and hippocampus, respectively. These studies demonstrate that accessory Proteins define AMPA receptor pharmacology by functionally linking allosteric AMPA receptor potentiator and antagonist sites.
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functional studies and distribution define a family of transmembrane ampa receptor Regulatory Proteins
Journal of Cell Biology, 2003Co-Authors: Susumu Tomita, Lu Chen, Yoshimi Kawasaki, Ronald S Petralia, Robert J Wenthold, Roger A Nicoll, David S BredtAbstract:Functional expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane Proteins. Here, we define a family of transmembrane AMPA receptor Regulatory Proteins (TARPs), which comprise stargazin, γ-3, γ-4, and γ-8, but not related Proteins, that mediate surface expression of AMPA receptors. TARPs exhibit discrete and complementary patterns of expression in both neurons and glia in the developing and mature central nervous system. In brain regions that express multiple isoforms, such as cerebral cortex, TARP–AMPA receptor complexes are strictly segregated, suggesting distinct roles for TARP isoforms. TARPs interact with AMPA receptors at the postsynaptic density, and surface expression of mature AMPA receptors requires a TARP. These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.
Wen-chao Song - One of the best experts on this subject based on the ideXlab platform.
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Membrane complement Regulatory Proteins.
Clinical Immunology, 2005Co-Authors: David D. Kim, Wen-chao SongAbstract:A number of Proteins anchored on the cell surface function to protect host tissues from bystander injury when complement is activated. In humans, they include decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and CD59. Although disease conditions directly attributable to abnormal function of these Proteins are relatively rare, it has become evident from recent studies using animal models that membrane complement Regulatory Proteins are important modulators of tissue injury in many autoimmune and inflammatory disease settings. Evidence is also emerging to support a role of these Proteins in regulating cellular immunity. In this article, we highlight recent advances on the in vivo biology of membrane complement Regulatory Proteins and discuss their relevance in human disease pathogenesis and therapeutics.
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Membrane complement Regulatory Proteins in autoimmune and inflammatory tissue injury.
Current Directions in Autoimmunity, 2003Co-Authors: Wen-chao SongAbstract:The complement system plays a complex role in the pathogenesis of autoimmune diseases. It inhibits autoimmunity development by helping to maintain self-tolerance and/or by facilitating the disposal of immune complexes and apoptotic cell antigens. On the other hand, complement activation is thought to contribute significantly to end organ damage in antibody-mediated autoimmune and inflammatory conditions, although the relevant importance of complement and Fe receptor pathways in these processes has recently been debated. To avoid autologous complement-mediated tissue injury, host cells normally express a number of soluble and membrane-bound complement Regulatory Proteins. Recent studies with gene knockout mice have suggested that membrane-bound complement Regulatory Proteins may critically determine the sensitivity of host tissues to complement injury in autoimmune and inflammatory disorders. Evidence is also accumulating to support the hypothesis that membrane complement Regulatory Proteins may not only inhibit complement-mediated injury during the effector phase of autoimmunity but also influence the adaptive immune response through complement-dependent or -independent mechanisms. The latter mechanism is likely related to their potential as cell surface signaling molecules.
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membrane complement Regulatory Proteins insight from animal studies and relevance to human diseases
International Complement Workshop, 2001Co-Authors: Takashi Miwa, Wen-chao SongAbstract:The complement system plays an important role in host defense. However, if not properly regulated, activated complement can also cause significant damage to host tissues, To prevent complement-mediated autologous tissue damage, host cells express a number of membrane-bound complement Regulatory Proteins, These include decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and CD59. Recent studies of membrane complement Regulatory Proteins from various animal species have revealed similarities as well as significant differences from the corresponding human Proteins, In this review, we summarize recent advances in this area and contrast the structure, function and tissue distribution of membrane complement Regulatory Proteins in human and nonprimate mammalian species. We also discuss how the characterization of the animal Proteins has provided important clues and might continue to show relevance to the pathogenesis and therapeutics of a number of human diseases.
Thomas Loning - One of the best experts on this subject based on the ideXlab platform.
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expression and prognostic value of the cell cycle Regulatory Proteins rb p16mts1 p21waf1 p27kip1 cyclin e and cyclin d2 in ovarian cancer
International Journal of Gynecological Pathology, 2003Co-Authors: Karin Mildelangosch, Maria Hagen, Anamaria Bamberger, Thomas LoningAbstract:Summary:To investigate the role of cell-cycle Regulatory Proteins in ovarian cancer, we performed immunohistochemistry for the cell-cycle promoters cyclin E and cyclin D2 and the cell-cycle inhibitors, Rb, p16MTS1, p21WAF1, and p27 KIP1, in 93 ovarian carcinomas (77 with follow-up data). The results
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expression of cell cycle Regulatory Proteins in endometrial carcinomas correlations with hormone receptor status and clinicopathologic parameters
Journal of Cancer Research and Clinical Oncology, 2001Co-Authors: Karin Mildelangosch, Anamaria Bamberger, Christoph Goemann, Elena Rossing, Gabriele Rieck, Bianca Kelp, Thomas LoningAbstract:Purpose: The normal human endometrium is characterized by hormone-dependent variations in the levels of cell-cycle Regulatory Proteins during the menstrual cycle. As this tightly controlled system is disturbed in endometrial carcinomas, we analyzed which cell-cycle regulators are involved in endometrial carcinogenesis. Methods: We performed Western blot analysis of five cell-cycle stimulating (cyclins D1, E, B1, cdk2, cdk4) and three cell-cycle inhibiting (p16INK4a, p21WAF1, Rb) Proteins in 41 endometrial carcinoma specimens. In addition, expression of the estrogen and progesterone receptors (ER, PR), Ki67, and, in selected cases, p16, cyclin E, and cyclin B1 was studied by immunohistochemistry. Results: We found upregulation of all analyzed cell-cycle regulators in most tumors compared to normal endometrial tissue samples. Overexpression of cyclin E, cyclin B1, and p21 was associated with a less differentiated phenotype. In addition, high levels of cyclin E, cdk2, and cdk4 correlated with weak/absent ER expression, and p16 and p21 overexpression was significantly associated with low PR immunoreactivity. Cyclin B1 expression correlated with cyclin E, cdk2, cdk4, p21, Rb, and Ki67, and cyclin E expression with cyclin D1 and Rb. Conclusions: We conclude that cyclin E and cyclin B1 might be the major cell-cycle regulators involved in proliferation and reduced differentiation of endometrial carcinomas. In addition, p16, p21, and Rb appear to be uncoupled from their normal cell-cycle inhibiting function in many endometrial carcinomas.
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expression of cell cycle Regulatory Proteins rb p16 mts1 p27 kip1 p21 waf1 cyclin d1 and cyclin e in breast cancer correlations with expression of activating protein 1 family members
International Journal of Cancer, 2000Co-Authors: Karin Mildelangosch, Anamaria Bamberger, Gabriele Rieck, Carola Methner, Thomas LoningAbstract:The activating protein-1 (AP-1) complex is a mitogen-activated composite transcription factor that leads to activation of various target genes and enhanced proliferation of many cells after stimulation by TPA, EGF, serum, etc. The molecular mechanism of cell-cycle activation by AP-1 complexes remains unclear. Therefore, we studied protein expression of 6 cell cycle–Regulatory Proteins (Rb, p16, p21, p27, cyclin D1, and cyclin E) in protein extracts from 53 breast cancer samples and 4 mammary cell lines and correlated the data with expression of the 7 AP-1 family members (c-jun, junB, junD, c-fos, fosB, fra-1, and fra-2) as determined in a previous study. After Western blot analysis, we found significant associations between members of both groups: whereas c-jun was associated with Rb expression (p = 0.002), strong junD and c-fos expression correlated with high cyclin E reactivity (p = 0.017 and p = 0.013, respectively). Over-expression of fosB was found mainly in tumors with strong Rb (p = 0.013) and weak p16 (p = 0.004) expression. Fra-1 expression was significantly associated with p16 and cyclin E over-expression, whereas fra-2 results correlated with both cyclin D1 and cyclin E. These results point to direct or indirect activation of some cell cycle–Regulatory Proteins by AP-1 complexes. In addition, our data suggest differential regulation of cell cycle–stimulating and –inhibiting factors depending on the abundance of single AP-1 family members. Int. J. Cancer 87:468–472, 2000. © 2000 Wiley-Liss, Inc.
C H Holmes - One of the best experts on this subject based on the ideXlab platform.
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complement Regulatory Proteins at the feto maternal interface during human placental development distribution of cd59 by comparison with membrane cofactor protein cd46 and decay accelerating factor cd55
European Journal of Immunology, 1992Co-Authors: C H Holmes, K L Simpson, Hidechika Okada, Noriko Okada, S D Wainwright, Damian F J Purcell, James M HoulihanAbstract:The complement (C) Regulatory Proteins decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), which control C3 convertases, together with CD59, an inhibitor of the membrane attack complex (MAC), were found to be present in the developing human placenta from at least 6 weeks of gestation until term. Immunostaining revealed differences in the distribution of these Proteins on the fetally derived trophoblast epithelium, especially in early placentae which contain trophoblast populations of diverse proliferative potential and differentiation status. Expression of all three Proteins occurred on the terminally differentiated syncytiotrophoblast epithelium covering chorionic villi and which is in direct contact with maternal blood. CD59 was also expressed on the underlying villous cytotrophoblast cells and on their extra-villous derivatives. These two populations showed differential expression of the C3 convertase regulators. Villous cytotrophoblast cells expressed MCP but were largely devoid of DAF. Proliferation of this population to generate extra-villous cytotrophoblast cell columns was associated with both an increase in DAF expression and a decrease in MCP expression. Throughout placental development, expression of DAF appeared to be lower than that of MCP and CD59 as assessed by solid-phase binding assays on isolated trophoblast membranes. Early placentae were also found to contain both DAF+ and DAF- chorionic villi. Conversely, expression of CD59 appeared comparatively high and transcripts for CD59 were found to be much more abundant than those for DAF in purified trophoblast cells. C Regulatory Proteins appear to play an important role throughout gestation in protecting the fetally derived human conceptus from maternal C. The differential expression patterns of the Proteins on trophoblast may reflect differences in requirement for specific functional activities at different locations within the placenta.
John H. Exton - One of the best experts on this subject based on the ideXlab platform.
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cell signalling through guanine nucleotide binding Regulatory Proteins g Proteins and phospholipases
FEBS Journal, 1997Co-Authors: John H. ExtonAbstract:Phospholipases are important enzymes in cell signal transduction since they hydrolyze membrane phospholipids to generate signalling molecules. Heterotrimeric guanine-nucleotide-binding Regulatory Proteins (G Proteins) play a major role in their regulation by a variety of agonists that activate receptors with seven membrane-spanning domains. Phospholipases of the C type, which hydrolyze inositol phospholipids to yield inositol trisphosphate and diacylglycerol, are regulated by the α and βγ subunits of certain heterotrimeric G Proteins as well as by receptor-associated and non-receptor-associated tyrosine kinases. Phospholipases of the D type, which hydrolyze phosphatidylcholine to phosphatidic acid, are regulated by members of the ADP-ribosylation factor and Rho subfamilies of small G Proteins, and by protein kinase C and other factors. This review presents recent information concerning the molecular details of G protein regulation of these phospholipases.
