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PubMed2002

The nucleolar remodeling complex NoRC mediates heterochromatin formation and silencing of ribosomal gene transcription.

Epigenetic control mechanisms silence about half of the ribosomal RNA (rRNA) genes in metabolically active cells. In exploring the mechanism by which the active or silent state of rRNA genes is inherited, we found that NoRC, a nucleolar remodeling complex containing Snf2h (also called Smarca5, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a, member 5), represses rDNA transcription. NoRC mediates rDNA silencing by recruiting DNA methyltransferase and histone deacetylase activity to the rDNA promoter, thus establishing structural characteristics of heterochromatin such as DNA methylation, histone hypoacetylation and methylation of the Lys9 residue of histone H3. These results indicate that active and inactive rRNA genes can be demarcated by their associated proteins, and link chromatin remodeling to DNA methylation and specific histone modifications.

3T3 Cells↗
PubMed1985

Classification of urticaria and the reactive inflammatory vascular dermatoses.

The common feature of all the conditions discussed in this article is that they are inflammatory vascular dermatoses that may occur as reactive processes in association with other diseases. The histopathologic characteristics of the lesions range from mild, perivascular dermal infiltration with inflammatory cells and vasodilation to various degrees of vessel damage (endothelial swelling to fibrinoid necrosis). The vessel damage is reflected in varying degrees of secondary changes including extravasation of edema fluid, extravasation of erythrocytes, epidermal necrosis, separation of the dermal-epidermal junction zone, and widespread tissue necrosis. The etiology of most of these conditions is still unknown, although strong evidence indicates that type III (circulating immune-complex-mediated) pathogenesis may be responsible for necrotizing venulitis (leukocytoclastic vasculitis) and that a type I (IgE-mediated) pathogenesis may be involved in some types of urticaria. For many of the reactions described, the patients have serum sickness-like systemic signs and symptoms in addition to cutaneous lesions, and a circulating immune-complex-mediated pathogenesis has been considered. Future investigations must address the types of antigens and antibodies present in the circulating immune complexes, the detection of specific antigen in cutaneous blood vessels, the reproduction of lesions in experimental animals, and the mechanisms responsible for the spectrum of clinicopathologic lesions produced, with special attention to the possibility that vessel damage results from circulating immune complex-induced lymphocytic rather than only leukocytoclastic vasculitis.

Angioedema↗
PubMed1993

Elements of the Drosophila bithorax complex that mediate repression by Polycomb group products.

The Polycomb (Pc) group genes encode repressors that restrict expression of homeotic genes to precise domains along the anterior-posterior (A-P) axis. We describe germ-line transformation constructs, containing portions of the bxd, iab-2, or iab-3 regulatory regions of the bithorax complex (BX-C), that are controlled by Pc group products in embryos. There are multiple BX-C elements that mediate Pc group control, which we call Pc group response elements (PREs), and they can work when removed from the normal BX-C context. These constructs are each regulated by the genes Polycomb (Pc), extra sex combs (esc), Enhancer of zeste (E[z]), polyhomeotic (ph), Polycomb-like (Pcl), Sex comb on midleg (Scm), Posterior sex combs (Psc), and Additional sex combs (Asx), consistent with multiple Pc group products acting together. Depending upon context, a PRE from the iab-3 region can restrict expression in different A-P positions. Thus, PREs are not specialized for particular parasegments, suggesting that Pc group products do not directly specify A-P boundaries of homeotic expression. Instead, the results support the idea that Pc group products provide stable memory or imprinting of boundaries which are initially specified by gap and pair-rule regulators.

Animals↗
PubMed1983

Circulating immune complexes and dermatologic diseases.

Immune complexes are products formed by the noncovalent union of antibody and antigen. Formation of immune complexes usually benefits the host by clearing antigens from the circulation. In some instances however, immune complexes are deposited in tissues with subsequent inflammation and tissue damage. The physiochemical characteristics of the immune complex, the status of the host's reticuloendothelial system, and the duration of exposure to antigen all influence the possibility of immune complex-mediated damage to tissues. Examples of this mechanism of injury are seen in serum sickness, systemic lupus erythematosus, and leukocytoclastic vasculitis. It is likely that the development of sensitive and reliable antigen-specific tests will provide more definitive information about the analysis of immune complex mediated injury.

Antigen-Antibody Complex↗
PubMed1994

Model for a DNA-mediated synaptic complex suggested by crystal packing of gamma delta resolvase subunits.

The packing arrangement of the 12 subunits of intact gamma delta resolvase in the unit cell of a hexagonal crystal form suggests a model for site-specific recombination that involves a DNA-mediated synaptic intermediate. The crystal structure has been determined by molecular replacement and partially refined at 2.8/3.5 A resolution. Although the small DNA-binding domain is disordered in these crystals, packing considerations show that only a small region of space in the crystal could accommodate a domain of its size. A family of related models for a synaptic complex between two DNA duplexes and 12 monomers that are arranged as situated in the crystal is consistent with the known topology of the complex and the distances between the three resolvase dimer-binding sites per DNA; further, these models place the two DNA recombination sites in contact with each other between two resolvase dimers, implying that strand exchange is accomplished through direct DNA-DNA interaction. A major role postulated, then, for the resolvase protein assembly is to stabilize a res DNA structure that is close to the topological transition state of the reaction.

Crystallography, X-Ray↗
PubMed1989

Passive transfer of antiviral antibodies restricts replication of Aleutian mink disease parvovirus in vivo.

When mink kits were infected neonatally with a highly virulent strain of Aleutian disease virus (ADV), 100% of both Aleutian and non-Aleutian genotype mink died of interstitial pneumonia characterized by permissive ADV infection of alveolar type II cells. Treatment of infected kits with either mink anti-ADV gamma globulin or mouse monoclonal antibodies against ADV structural proteins reduced mortality by 50 to 75% and drastically reduced the severity of clinical signs. Interestingly, mink kits that survived the acute pulmonary disease all developed the chronic form of immune complex-mediated Aleutian disease. Thus, the antibodies directed against ADV structural proteins were capable of modulating the in vivo pathogenicity from an acute fulminant disease to a chronic immune complex-mediated disorder. The mechanism of this modulation was examined by strand-specific in situ hybridization. We found that the number of ADV-infected type II cells was the same in both untreated and antibody-treated kits. However, in the treated kits, viral replication and transcription were restricted at the cellular level. These data suggested that antibodies prevented acute viral pneumonia by restricting the intracellular level of viral replication and that the relevant antigenic determinants were contained within the viral structural proteins. The restricted levels of viral replication and transcription seen in antibody-treated mink kits resembled the levels observed in infected adult mink and suggested a role of antiviral antibodies in development of persistent infection and chronic immune complex disease.

Acute Disease↗
PubMed2004

A Rickettsia WASP-like protein activates the Arp2/3 complex and mediates actin-based motility.

Spotted fever group Rickettsia are obligate intracellular pathogens that exploit the host cell actin cytoskeleton to promote motility and cell-to-cell spread. Although other pathogens such as Listeria monocytogenes use an Arp2/3 complex-dependent nucleation mechanism to generate comet tails consisting of Y-branched filament arrays, Rickettsia polymerize tails consisting of unbranched filaments by a previously unknown mechanism. We identified genes in several Rickettsia species encoding proteins (termed RickA) with similarity to the WASP family of Arp2/3-complex activators. Rickettsia rickettsii RickA activated both the nucleation and Y-branching activities of the Arp2/3 complex like other WASP-family proteins, and was sufficient to direct the motility of microscopic beads in cell extracts. Actin tails generated by RickA-coated beads consisted of Y-branched filament networks. These data suggest that Rickettsia use an Arp2/3 complex-dependent actin-nucleation mechanism similar to that of other pathogens. We propose that additional Rickettsia or host factors reorganize the Y-branched networks into parallel arrays in a manner similar to a recently proposed model of filopodia formation.

Actin Cytoskeleton↗
PubMed1998

Mechanisms of cell signaling in immune-mediated inflammation.

Deposition of immune complexes in tissues is the pathogenic mechanism underlying tissue injury in a number of diverse clinical conditions affecting the skin, joints, blood vessels and renal glomeruli. Initial approaches to the understanding of these conditions have stressed the roles of both the activation of the complement system and the accumulation of polymorphonuclear leukocytes as the main molecular and cellular mechanisms explaining the sequence of events leading to tissue damage. Recent findings on (i) the molecular biology of the leukocyte chemoattractants, (ii) the chemical structure and function of receptors for the Fc portion of the antibody molecule and (iii) the signaling events coupled to the engagement of these receptors have led to an understanding of the biochemical events involved in immune-complex injury and have provided a promising avenue for the development of therapeutic approaches. This review will focus on our current understanding of signal transduction events in the effector phase of immune-complex-mediated tissue injury.

Anaphylatoxins↗
PubMed1995

Monocyte Fc gamma receptor cross-linking induces IL-8 production.

In response to bacterial cell wall products such as LPS, monocytes produce IL-8, a powerful neutrophil chemotaxin. However, in the absence of bacterial pathogens, immune complex-mediated diseases such as rheumatoid arthritis are associated with high levels of IL-8 in monocyte-rich compartments. Since it is known that IgG-containing immune complexes can recruit neutrophils via an Fc gamma R-dependent process, we hypothesized that cross-linking of monocyte Fc gamma receptors may induce IL-8. To test this hypothesis, peripheral blood mononuclear cells were evaluated for IL-8 induction in response to immobilized LPS-free pooled human IgG. Immobilized IgG, but not soluble IgG, induced IL-8 in a dose-dependent manner (p < 0.05, r = 0.99). This induction corresponded with an up-regulation in IL-8 steady state mRNA levels that peaked at 4 h. The released IL-8 was functional, since supernatants induced concentration-dependent neutrophil migration that was inhibited by a monoclonal anti-IL-8 Ab. Evaluation of purified monocytes for IL-8 production, as well as FACS analysis of IgG-stimulated PBMC preparations, demonstrated that monocytes are the principal IL-8 producer cell. Thus, monocyte Fc gamma R cross-linking induces biologically active IL-8, which may participate in the pathogenesis of immune complex-mediated diseases.

Cells, Cultured↗
PubMed1985

Interaction of asialo von Willebrand factor with glycoprotein Ib induces fibrinogen binding to the glycoprotein IIb/IIIa complex and mediates platelet aggregation.

von Willebrand factor (vWF) is necessary for the initial attachment of platelets to exposed subendothelium, particularly under flow conditions like those prevailing in the microcirculation. Little is known about its possible participation in subsequent events leading to formation of platelet thrombi at sites of vascular injury. We addressed this question by studying the mechanisms by which desialylated vWF induces platelet aggregation in the absence of any other stimulus. Asialo vWF, unlike the native molecule, does not require ristocetin to interact with platelets. Agglutination induced by ristocetin is largely independent of active platelet metabolism and only partially reflects physiological events. We have shown here that binding of asialo vWF to platelets was accompanied by release of dense granule content and subsequent ADP-dependent fibrinogen binding to receptors on the glycoprotein (GP) IIb/IIIa complex. The initial interaction of asialo vWF with platelets was mediated by GPIb, as shown by blocking obtained with monoclonal antibody. Inhibition of this initial interaction completely abolished platelet aggregation induced by asialo vWF. The same effect was obtained with a monoclonal anti-GPIIb/IIIa antibody. This, however, did not block asialo vWF binding to platelets, but rather inhibited subsequent fibrinogen binding induced by asialo vWF. Therefore, the latter process was also essential for platelet aggregation under the conditions described. At saturation, asialo vWF induced binding of between 3.2 and 27.7 X 10(3) fibrinogen molecules/platelet, with an apparent dissociation constant between 0.28 and 1.18 X 10(-6) M. This study shows that asialo, and possibly native, vWF acts as a platelet agonist after its binding to GPIb and induces aggregation through a pathway dependent on GPIIb/IIIa-related receptors.

Asialoglycoproteins↗
PubMed2003

A role for cofactor-cofactor and cofactor-histone interactions in targeting p300, SWI/SNF and Mediator for transcription.

Transcriptional activation from chromatin by nuclear receptors (NRs) requires multiple cofactors including CBP/p300, SWI/SNF and Mediator. How NRs recruit these multiple cofactors is not clear. Here we show that activation by androgen receptor and thyroid hormone receptor is associated with the promoter targeting of SRC family members, p300, SWI/SNF and the Mediator complex. We show that recruitment of SWI/SNF leads to chromatin remodeling with altered DNA topology, and that both SWI/SNF and p300 histone acetylase activity are required for hormone-dependent activation. Importantly, we show that both the SWI/SNF and Mediator complexes can be targeted to chromatin by p300, which itself is recruited through interaction with SRC coactivators. Furthermore, histone acetylation by CBP/p300 facilitates the recruitment of SWI/SNF and Mediator. Thus, our data indicate that multiple cofactors required for activation are not all recruited through their direct interactions with NRs and underscore a role of cofactor-cofactor interaction and histone modification in coordinating the recruitment of multiple cofactors.

Acetylation↗
PubMed1981

Hepatitis B as an immune complex disease.

Evidence has accumulated which indicates that several of the extrahepatic syndromes associated with HBV infection--the prodromal arthritis-dermatitis syndrome, systemic necrotizing vasculitis, and glomerulonephritis--result from immune complex-mediated injury; however, our understanding of their pathogenesis remains incomplete. Other disorders--essential mixed cryoglobulinemia and polymyalgia rheumatica--have also been linked to HBV, but these associations are more controversial. In most patients with HBV infection, circulating immune complexes are of no pathogenetic importance, but may reflect normal mechanisms for immune clearance of viral antigens. Little insight has been gained into the factors which predispose to immune complex-mediated tissue injury in only a small proportion of patients with type B hepatitis, and few options are available for the management of patients with these extrahepatic disorders. Finally, circulating immune complexes do not appear to contribute to the pathogenesis of liver disease associated with HBV infection.

Glomerulonephritis↗
PubMed2001

Structural and functional analysis of an mRNP complex that mediates the high stability of human beta-globin mRNA.

Human globins are encoded by mRNAs exhibiting high stabilities in transcriptionally silenced erythrocyte progenitors. Unlike alpha-globin mRNA, whose stability is enhanced by assembly of a specific messenger RNP (mRNP) alpha complex on its 3' untranslated region (UTR), neither the structure(s) nor the mechanism(s) that effects the high-level stability of human beta-globin mRNA has been identified. The present work describes an mRNP complex assembling on the 3' UTR of the beta-globin mRNA that exhibits many of the properties of the stability-enhancing alpha complex. The beta-globin mRNP complex is shown to contain one or more factors homologous to alphaCP, a 39-kDa RNA-binding protein that is integral to alpha-complex assembly. Sequence analysis implicates a specific 14-nucleotide pyrimidine-rich track within its 3' UTR as the site of beta-globin mRNP assembly. The importance of this track to mRNA stability is subsequently verified in vivo using mice expressing human beta-globin transgenes that contain informative mutations in this region. In combination, the in vitro and in vivo analyses indicate that the high stabilities of the alpha- and beta-globin mRNAs are maintained through related mRNP complexes that may share a common regulatory pathway.

3' Untranslated Regions↗
PubMed2000

Role of SNAP23 in insulin-induced translocation of GLUT4 in 3T3-L1 adipocytes. Mediation of complex formation between syntaxin4 and VAMP2.

Both syntaxin4 and VAMP2 are implicated in insulin regulation of glucose transporter-4 (GLUT4) trafficking in adipocytes as target (t) soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) and vesicle (v)-SNARE proteins, respectively, which mediate fusion of GLUT4-containing vesicles with the plasma membrane. Synaptosome-associated 23-kDa protein (SNAP23) is a widely expressed isoform of SNAP25, the principal t-SNARE of neuronal cells, and colocalizes with syntaxin4 in the plasma membrane of 3T3-L1 adipocytes. In the present study, two SNAP23 mutants, SNAP23-DeltaC8 (amino acids 1 to 202) and SNAP23-DeltaC49 (amino acids 1 to 161), were generated to determine whether SNAP23 is required for insulin-induced translocation of GLUT4 to the plasma membrane in 3T3-L1 adipocytes. Wild-type SNAP23 (SNAP23-WT) promoted the interaction between syntaxin4 and VAMP2 both in vitro and in vivo. Although SNAP23-DeltaC49 bound to neither syntaxin4 nor VAMP2, the SNAP23-DeltaC8 mutant bound to syntaxin4 but not to VAMP2. In addition, although SNAP23-DeltaC8 bound to syntaxin4, it did not mediate the interaction between syntaxin4 and VAMP2. Moreover, overexpression of SNAP23-DeltaC8 in 3T3-L1 adipocytes by adenovirus-mediated gene transfer inhibited insulin-induced translocation of GLUT4 but not that of GLUT1. In contrast, overexpression of neither SNAP23-WT nor SNAP23-DeltaC49 in 3T3-L1 adipocytes affected the translocation of GLUT4 or GLUT1. Together, these results demonstrate that SNAP23 contributes to insulin-dependent trafficking of GLUT4 to the plasma membrane in 3T3-L1 adipocytes by mediating the interaction between t-SNARE (syntaxin4) and v-SNARE (VAMP2).

3T3 Cells↗
PubMed2004

Adaptor protein complex 1 mediates the transport of lysosomal proteins from a Golgi-like organelle to peripheral vacuoles in the primitive eukaryote Giardia lamblia.

Giardia lamblia is an early branching protist that possesses peripheral vacuoles (PVs) with characteristics of lysosome-like organelles, located underneath the plasma membrane. In more evolved cells, lysosomal protein trafficking is achieved by cargo recognition involving adaptor protein (AP) complexes that recognize specific amino acid sequences (tyrosine and/or dileucine motifs) within the cytoplasmic tail of membrane proteins. Previously, we reported that Giardia has a tyrosine-based sorting system, which mediates the targeting of a membrane-associated cysteine protease (encystation-specific cysteine protease, ESCP) to the PVs. Here, we show that Giardia AP1 mediates the transport of ESCP and the soluble acid phosphatase (AcPh) to the PVs. By using the yeast two-hybrid assay we found that the ESCP tyrosine-based motif interacts specifically with the medium subunit of AP1 (Gimicroa). Hemagglutinin-tagged Gimicroa colocalizes with ESCP and AcPh and coimmunoprecipitates with clathrin, suggesting that protein trafficking toward the PVs is clathrin-adaptin dependent. Targeted disruption of Gimicroa results in mislocalization of ESCP and AcPh but not of variant-specific surface proteins. Our results suggest that, unlike mammalian cells, only AP1 is involved in anterograde protein trafficking to the PVs in Giardia. Moreover, even though Giardia trophozoites lack a morphologically discernible Golgi apparatus, the presence of a clathrin-adaptor system suggests that this parasite possess a primitive secretory organelle capable of sorting proteins similar to that of more evolved cells.

Acid Phosphatase↗
PubMed2000

Contributions of C3H6O+. ions with the oxygen on the middle carbon to gas phase ion chemistry

The numerous ways in which studies of C3H6O+. ions with the oxygen on the second carbon have added to our knowledge of gas phase ion chemistry are reviewed. The enol form of this ion (1) first attracted interest during early investigations of the mechanism of the McLafferty Rearrangement and later in characterizing the double McLafferty Rearrangement. Next, it was found that 1 isomerizes to the higher energy acetone ion (2). This discovery sparked studies of the relative stabilities of ionized and neutral enol and ketone species. It also led to the discovery that 1-->2 surmounts a substantial barrier, and that 2 dissociates faster than the excess energy deposited in it by the isomerization can become randomly distributed; i.e., dissociation following 1-->2 is nonergodic. This fact is manifested by a more abundant loss of the methyl formed by isomerization and a greater associated translational energy release. Propene oxide and methyl vinyl ether ions also appear to ionize to 2 and to dissociate nonergodically. Methane is eliminated from 2 through a methyl-acetyl ion complex. Characterization of this reaction by photoionization mass spectrometry, ab initio theory, and RRKM calculations helped to establish that complex-mediated alkane eliminations are generally confined to a region just above threshold. At higher energies, because attractions between ions and nonpolar neutrals are weak, simple dissociation is too fast for complex-mediated H-transfer to compete with it. Studies of the collision-induced dissociations of 2 demonstrate that the first electronically excited A state of 2 is very long-lived and efficiently releases its energy into translational energy when the ion collides with a neutral at low impact energies. Finally, ion-molecule reactions of 2 and acetone-containing ion clusters in the gas phase are described.

Journal Article↗
PubMed2003

Positional cloning of the young mutation identifies an essential role for the Brahma chromatin remodeling complex in mediating retinal cell differentiation.

Zebrafish with the young (yng) mutation show a defect in retinal cell differentiation. Here we demonstrate that a mutation in a brahma-related gene (brg1) is responsible for the yng phenotype. Brahma homologues function as essential subunits for SWI/SNF-type chromatin remodeling complexes. Our analysis indicates that brg1 is required for the wave of mitogen-activated protein kinase activity that precedes retinal cell differentiation. Using specific inhibitors of the mitogen-activated protein kinase pathway we show this signal has a direct role in retinal cell differentiation. Lastly, through investigations of mutants in other chromatin remodeling subunits, we provide genetic evidence for gene and tissue specificity of the Brahma chromatin remodeling complex.

Animals↗
PubMed2003

Attenuation of cell adhesion in lymphocytes is regulated by CYTIP, a protein which mediates signal complex sequestration.

An important theme in molecular cell biology is the regulation of protein recruitment to the plasma membrane. Fundamental biological processes such as proliferation, differentiation or leukocyte functions are initiated and controlled through the reversible binding of signaling proteins to phosphorylated membrane components. This is mediated by specialized interaction modules, such as SH2 and PH domains. Cytohesin-1 is an intracellular guanine nucleotide exchange factor, which regulates leukocyte adhesion. The activity of cytohesin-1 is controlled by phospho inositide-dependent membrane recruitment. An interacting protein was identified, the expression of which is upregulated by cytokines in hematopoietic cells. This molecule, CYTIP, is also recruited to the cell cortex by integrin signaling via its PDZ domain. However, stimulation of Jurkat cells with phorbol ester results in re-localization of CYTIP to the cytoplasm, and membrane detachment of cytohesin-1 strictly requires co-expression of CYTIP. Consequently, stimulated adhesion of Jurkat cells to intracellular adhesion molecule-1 is repressed by CYTIP. These findings outline a novel mechanism of signal chain abrogation through sequestration of a limiting component by specific protein-protein interactions.

Adenosine Triphosphate↗