Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitosis in animals starts with the disassembly of the nuclear pore complexes and the breakdown of the nuclear envelope. In contrast to many fungi, the corn smut fungus Ustilago maydis also removes the nuclear envelope. Here, we report on the dynamic behavior of the nucleoporins Nup214, Pom152, Nup133, and Nup107 in this "open" fungal mitosis. In prophase, the nuclear pore complexes disassembled and Nup214 and Pom152 dispersed in the cytoplasm and in the endoplasmic reticulum, respectively. Nup107 and Nup133 initially spread throughout the cytoplasm, but in metaphase and early anaphase occurred on the chromosomes. In anaphase, the Nup107-subcomplex redistributed to the edge of the chromosome masses, where the new envelope was reconstituted. Subsequently, Nup214 and Pom152 are recruited to the nuclear pores and protein import starts. Recruitment of nucleoporins and protein import reached a steady state in G2 phase. Formation of the nuclear envelope and assembly of nuclear pores occurred in the absence of microtubules or F-actin, but not if both were disrupted. Thus, the basic principles of nuclear pore complex dynamics seem to be conserved in organisms displaying open mitosis.
Mol Biol Cell 2008 Mar
PMID:Dynamic rearrangement of nucleoporins during fungal "open" mitosis. 1817 26

The extrinsic apoptosis pathway is activated when certain members of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) are oligomerized by their cognate ligands that are members of the TNF superfamily (TNFSF). The apoptosis-inducing capacity of a member of the TNFRSF relies on the presence of a death domain (DD) in the intracellular portion of the receptor protein. Such receptors are also referred to as death receptors. Binding of a TNFSF ligand to a TNFRSF receptor that is expressed on the surface of a cell results in the formation of a receptor proximal protein complex. This protein complex is the platform for further signaling events within the cell. In case of death receptors like TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1/DR4), TRAIL-R2 (KILLER/APO-2/DR5/TRICK), CD95 (Fas, APO-1), or TNF receptor 1 (TNF-R1), this complex is termed death-inducing signaling complex (DISC). The compositions of the various DISCs have been intensively studied in the last 12 years. For the CD95 and the TRAIL-R1/R2 DISCs, it is now clear that the adaptor protein Fas-associated DD protein (FADD) forms part of these complexes and is necessary for recruitment of the proapoptotic signaling molecules caspase-8 and caspase-10. Recruitment of these proteases allows for their activation at the DISC and subsequent induction of apoptosis. The caspase-8 homologous cellular FLICE-like inhibitory protein (cFLIP) can also be recruited to the DISC. cFLIP acts as an anti-apoptotic regulator by interfering with activation of caspases 8 and 10 at the DISC. Interestingly, treatment of TRAIL-resistant tumor cells with conventional chemotherapeutic drugs or with proteasome inhibitors renders these cells sensitive for TRAIL-induced apoptosis. By applying the methodology of the biochemical analysis of the TRAIL DISC described here, we were able to show that this sensitization is mainly due to changes in the biochemical composition of the DISC as the apoptosis-initiating protein complex of the extrinsic pathway.
Methods Mol Biol 2008
PMID:Biochemical analysis of the native TRAIL death-inducing signaling complex. 1817 22

Chronic consumption of ethanol induces hepatic steatosis and inflammation, which can eventually lead to more severe liver injury, characterized by fibrosis and cirrhosis. Recruitment of neutrophils to the liver, as well as activation of Kupffer cells, mediates the inflammatory responses observed after chronic ethanol exposure. Kupffer cells, the resident macrophages of the liver, are critical to the onset of ethanol-induced liver injury. Activation of Kupffer cells leads to an increased production of proinflammatory cytokines, such as tumor necrosis factor-alpha and also reactive oxygen species, a process mediated in part by changes in lipopolysaccharide-induced TLR4-dependent signal transduction. The isolation and culture of Kupffer cells is an important technique with which one can elucidate the mechanisms that contribute to alcoholic liver injury.
Methods Mol Biol 2008
PMID:Isolation of Kupffer cells from rats fed chronic ethanol. 1836 21

Interferon-gamma IFN-gamma)-induced remodeling of the bacterial phagosome for pathogen clearance elicits the aid of a new family of GTPases termed the p47 IRGs. Members of this group reside primarily on ER-Golgi membranes before translocating to the nascent phagosome within minutes of bacterial uptake. Recruitment of p47 IRGs coincides with the acquisition of phagosome maturation and autophagy markers as well as enhanced acidification of this organelle. Here we describe a simple spectrofluorometric assay to measure luminal acidification of the bacterial phagosome within intact cells such as macrophages. This method can be applied to study the phagosomal pH pH_pg) of activated cells infected with a variety of infectious microorganisms and the roles played by members of the p47 IRG family in auto)phagolysosome biogenesis.
Methods Mol Biol 2008
PMID:Bacterial phagosome acidification within IFN-gamma-activated macrophages: role of host p47 immunity-related GTPases IRGs). 1842 65

Recruitment of signaling molecules to the cytoplasmic domains of the CD3 subunits of the T-cell receptor (TCR) is crucial for early T-cell activation. These transient associations either do or do not require tyrosine phosphorylation of CD3 immune tyrosine activation motifs (ITAMs). Here we show that the non-ITAM-requiring adaptor protein Nck forms a complex with an atypical PxxDY motif of the CD3epsilon tail, which encompasses Tyr166 within the ITAM and a TCR endocytosis signal. As suggested by the structure of the complex, we find that Nck binding inhibits phosphorylation of the CD3epsilon ITAM by Fyn and Lck kinases in vitro. Moreover, the CD3epsilon-Nck interaction downregulates TCR surface expression upon physiological stimulation in mouse primary lymph node cells. This indicates that Nck performs an important regulatory function in T lymphocytes by inhibiting ITAM phosphorylation and/or removing cell surface TCR via CD3epsilon interaction.
J Mol Biol 2008 Jul 18
PMID:Structural and functional evidence that Nck interaction with CD3epsilon regulates T-cell receptor activity. 1855 70

The ubiquitination of the receptor that mediates signaling induced by the polypeptide pituitary hormone prolactin (PRL) has been shown to lead to the degradation of this receptor and to the ensuing negative regulation of cellular responses to PRL. However, the mechanisms of PRL receptor (PRLr) proteolysis remain largely to be determined. Here we provide evidence that PRLr is internalized and primarily degraded via the lysosomal pathway. Ubiquitination of PRLr is essential for the rapid internalization of PRLr, which proceeds through a pathway dependent on clathrin and the assembly polypeptide 2 (AP2) adaptor complexes. Recruitment of AP2 to PRLr is stimulated by PRLr ubiquitination, which also is required for the targeting of already internalized PRLr to the lysosomal compartment. While mass spectrometry analysis revealed that both monoubiquitination and polyubiquitination (via both K48- and K63-linked chains) occur on PRLr, the results of experiments using forced expression of ubiquitin mutants indicate that PRLr polyubiquitination via K63-linked chains is important for efficient interaction of PRLr with AP2 as well as for efficient internalization, postinternalization sorting, and proteolytic turnover of PRLr. We discuss how specific ubiquitination may regulate early and late stages of endocytosis of PRLr and of related receptors to contribute to the negative regulation of the magnitude and duration of downstream signaling.
Mol Cell Biol 2008 Sep
PMID:Polyubiquitination of prolactin receptor stimulates its internalization, postinternalization sorting, and degradation via the lysosomal pathway. 1857 76

Recruitment of activated T cells to the tubules is a defining feature of cell-mediated renal allograft rejection. Many of these intratubular T cells express the alphaE(CD103)beta7 integrin, potentially allowing adhesion to epithelial cells which express the only defined counter-receptor, E-cadherin. However, the potential of rejection-associated intratubular chemokines to modulate the adhesive function of this integrin has not been investigated. This study demonstrated that CCL7 is expressed within the tubules during renal allograft rejection. Modelling with CD103-expressing MOLT-16 T cells demonstrated chemotactic responses to the chemokines CXCL10, CXCL12, CCL5 and, most significantly, CCL7 (p<0.001); these responses were consistent with the expression of CXCR3, CXCR4 and CCR1 by these cells. A solid-phase adhesion assay showed little background binding of MOLT-16 cells to immobilised human E-cadherin.Fc fusion protein but alphaEbeta7 integrin-specific adhesion was greatly increased by the addition of either Mn2+ or 10nM CCL7 (p<0.01 or <0.001, respectively). Treatment of activated human peripheral T cells with TGFbeta1 for 3 days induced the expression of CD103 on a mean 53% of these cells; a similar proportion of CD103+ and CD103- T cells within these cultures expressed receptors for the chemokine CCL7. CD103+ T cell fractions were sorted from mitogen- or alloantigen-activated, TGFbeta1-treated T cell cultures and also showed specific enhancement of adhesion to E-cadherin.Fc fusion protein following stimulation with Mn2+ or 10nM CCL7 (p<0.01 in all cases); CD103- T cells were not adherent under any conditions. Together these data suggest that although the alphaEbeta7 integrin is induced on activated intratubular T cells by the presence of TGFbeta, the adhesive function of this integrin is promoted by the presence of chemokines such as CCL7, which are also expressed within tubules during renal allograft rejection.
Mol Immunol 2008 Sep
PMID:Renal allograft rejection: the contribution of chemokines to the adhesion and retention of alphaE(CD103)beta7 integrin-expressing intratubular T cells. 1864 41

Recruitment and retention of circulating progenitor cells at the site of injured or ischemic tissues facilitates adult neo-vascularization. We hypothesized that cell therapy could modulate local neo-vascularization through the vascular endothelial growth factor (VEGF)/stromal cell-derived factor-1 (SDF-1) axis and by paracrine effects on local endothelial cells. We isolated from rat bone marrow a subset of multipotent adult progenitor cell-derived progenitor cells (MDPC). In vitro, MDPCs secreted multiple cytokines related to inflammation and angiogenesis, including monocyte chemotactic protein-1, SDF-1, basic fibroblast growth factor, and VEGF, and expressed the chemokine receptors CXCR4 and VEGFR1. To investigate in vivo properties, we transplanted MDPCs into the ischemic hind limbs of rats. Elevated levels of the chemokine SDF-1 and colocalization of CD11b(+) cells marked the initial phase of tissue remodeling after cell transplantation. Prolonged engraftment was observed in the adventitial-medial border region of arterioles of ischemic muscles. However, engrafted cells did not differentiate into endothelial or smooth muscle cells. Limb perfusion normalized 4 weeks after cell injection. Inhibition of SDF-1 reduced the engraftment of transplanted cells and decreased endothelial cell proliferation. These findings suggest a two-stage model whereby transplanted MDPCs modulate wound repair through recruitment of inflammatory cells to ischemic tissue. This is an important potential mechanism for cell transplantation, in addition to the direct modulation of local vascular cells through paracrine mechanisms.
J Mol Med (Berl) 2008 Nov
PMID:VEGFR1/CXCR4-positive progenitor cells modulate local inflammation and augment tissue perfusion by a SDF-1-dependent mechanism. 1881 Mar 77

Plasmodium falciparum, the human malaria parasite, is evolutionarily distant from other eukaryotes. Genome-wide analyses of transcription-associated proteins have revealed a relative paucity of putative regulatory transcription factors and an abundance of putative chromatin remodeling machinery, suggesting that this parasite has a transcription regulatory system that is distinct from those of other eukaryotes. Here, we have analyzed transcriptional regulation of the peroxiredoxin genes, pf1-cys-prx and pftpx-1, which show different expression patterns in P. falciparum. The reporter assays revealed the presence of putative enhancers in the 5' regions of these genes. Although pf1-cys-prx shows trophozoite/schizont stage-specific transcription, a putative cis-acting enhancer sequence in pf1-cys-prx was constitutively active when inserted into the 5' region of pftpx-1. Electrophoretic mobility shift and DNase I footprinting assays showed that this enhancer region is the target of trophozoite/schizont stage-specific DNA binding proteins. In addition, chromatin immunoprecipitation assays showed that the increased levels of histone acetylation in the 5' region of pf1-cys-prx and pftpx-1 correlate with the transcriptional activity of these genes. Recruitment of PfGCN5 histone acetyltransferase to the pf1-cys-prx enhancer in trophozoite/schizont stage was observed. These results suggest that P. falciparum possesses a sophisticated system of transcriptional regulation during intraerythrocytic stages that is managed by coordinated interactions of unique cis-elements and trans-acting factors and chromatin modifications.
Mol Biochem Parasitol 2008 Nov
PMID:5' sequence- and chromatin modification-dependent gene expression in Plasmodium falciparum erythrocytic stage. 1869 28

Recruitment of eosinophils has long been recognized as a hallmark of the inflammatory response in asthma. However, the functions of this population of cells in host defense remain poorly understood. Eosinophils play an important part in the inflammatory response and have key regulatory roles in the afferent arm of the immune response. More recently, eosinophils have been demonstrated to participate in host defense against respiratory viruses. The specific contributions of eosinophils to the pathophysiology of asthma remain controversial. However, the balance of evidence indicates that they have a significant role in the disease, suggesting that they may be appropriate targets for therapy. Towards this end, a novel intervention of considerable potential interest is the use of an antibody directed against the beta common chain of the receptor for interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor. However, eliminating eosinophils may not be a risk-free therapeutic strategy, as there is potentially an increased likelihood of respiratory viral infections. This may predispose to the development of acute exacerbations of asthma, an outcome that would have significant clinical implications.
Curr Mol Med 2008 Sep
PMID:Targeting eosinophils in asthma. 1878 65


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