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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat peripheral nerve Schwann cells have been shown to express the alpha-chemokine receptor CXCR4 as well as the corresponding ligand stromal cell-derived factor-1 (SDF-1). We have investigated gene regulatory mechanisms acting on the expression of CXCR4 in cultured rat Schwann cells and found that receptor expression at transcript- and protein levels is directly dependent on intracellular cyclic AMP. Such increased levels of CXCR4 expression were found to be efficiently reversed by the action of tumor necrosis factor-alpha (TNFalpha). We also provide evidence that the POU box transcription factor Oct-6/SCIP is involved in the control of CXCR4 transcription. Finally, we could demonstrate that CXCR4 activation by SDF-1alpha increases the number of dying Schwann cells, indicating that this receptor/ligand interaction is modulating cell survival. Our data, therefore, suggest that in the Schwann cell lineage signal transduction cascades controlled by the activation of TNF- and CXCR4 receptors are functionally coupled.
Mol Cell Neurosci 2003 Sep
PMID:Cyclic AMP and tumor necrosis factor-alpha regulate CXCR4 gene expression in Schwann cells. 1455 Jul 64

Principally expressed on the surface of T lymphocytes, the chemokine and HIV receptor CXCR4 has been shown to serve key roles in both chemotaxis and HIV-1-entry into T cells. Understanding the regulation of CXCR4 expression is therefore of paramount importance to further elucidating its endogenous role and contributions to HIV-1 pathogenesis. Using an RNase protection assay (RPA), we have demonstrated that mitogenic stimulation of purified human peripheral blood T lymphocytes (PBL) decreased CXCR4 mRNA relative to unstimulated controls in a calcineurin-dependent manner; an expression pattern mimicked by the chemokine receptor CCR7. A change in transcriptional activity, not in mRNA stability, was required for control of CXCR4 and CCR7 expression. Changes in CXCR4 mRNA expression translated into a stimulation- and calcineurin-dependent decrease in cell surface CXCR4 expression. We have previously demonstrated that CXCR4 mRNA and protein is regulated by cAMP; here we show that calcium and calcineurin signaling pathways modify cAMP-driven changes. Moreover, we provide data supporting a role for the transcription factor YY1 in calcineurin-dependent regulation of CXCR4 expression.
Mol Immunol 2003 Dec
PMID:Regulation of CXCR4 expression in human T lymphocytes by calcium and calcineurin. 1456 73

Stromal cell-derived factor-1 (SDF-1), the only ligand of the CXCR4 receptor, is mainly known as a chemotactic factor for hematopoietic progenitor cells. However, studies of knock-out mice have shown malformation of different organ-systems suggesting that SDF-1 may have a role in angiogenesis and cardiac and cerebral development. However, the underlying mechanisms of its action are largely unknown. Therefore, we performed suppression subtractive hybridization (SSH) in order to identify genes that are differentially expressed after stimulation of human arterial endothelial cells (HUAEC) with SDF-1. Using SSH we found ten genes, with varied functions, whose mRNA expression is induced by SDF-1alpha in HUAEC. We show that SSH is a reliable method for identifying differentially expressed genes and that SDF-1alpha may have more functions than previously reported.
Mol Cell Probes 2003 Oct
PMID:The use of suppression subtractive hybridization for the study of SDF-1alpha induced gene-expression in human endothelial cells. 1458 Mar 99

Several human monoclonal antibodies can neutralize a range of human immunodeficiency virus type 1 (HIV-1) primary isolates but their potency and related ability to suppress generation of HIV-1 escape mutants is significantly lower than the activity of antiretroviral drugs currently in clinical use. Recently, a human Fab, X5, was identified and found to neutralize primary isolates from different clades. Further improvement of the potency and breadth of HIV-1 neutralization by this antibody could be critical for its potential use in the treatment of HIV-1-infected patients. However, increasing potency of an antibody by selection from libraries may lead to a decrease in the breadth of neutralization. In an attempt to solve this problem, we subjected a random mutagenesis library of the scFv X5 to sequential rounds of selection on non-homologous HIV-1 envelope glycoproteins (Envs) dubbed sequential antigen panning (SAP). By using SAP, we identified two scFv antibodies, m6 and m9, that were tested with a panel of 33 diverse primary HIV-1 infectious isolates in an assay based on a reporter cell-line expressing high levels of CD4, CCR5 and CXCR4. The IC(50) was less than 50 microg/ml for 21 (m6) and 19 (m9) out of 29 isolates from group M (subtypes A-C, F, G and CRF-01AE) and one isolate from group N; three isolates from group O were not significantly inhibited at 50 microg/ml. The average IC(50) values for the two antibodies were significantly (p<0.001, n=29) lower compared to scFv X5. Their inhibitory activity does not appear to be related to the HIV-1 subtype, coreceptor usage or the disease stage. m9 inhibited infection of peripheral blood mononuclear cells by the primary isolates JRCSF, 89.6 and BR020 with IC(90) of 4, 6 and 25 microg/ml, respectively; for a single-round infection by pseudovirus, the IC(90) for JRSCF, 89.6, YU2 and HXBc2 was 15, 5, 15 and 5 microg/ml, respectively. In these two assays the IC(90) for m9 was, on average, two- to threefold lower than for scFv X5. These results demonstrate that both the potency and the breadth of HIV-1 neutralization of one of the few known potent broadly cross-reactive human monoclonal antibodies, scFv X5, could be improved significantly. However, only experiments in animal models and clinical trials in humans will show whether these new scFvs and the approach for their identification have potential in the development of prophylactics and therapeutics for HIV-1 infections.
J Mol Biol 2004 Jan 02
PMID:Improved breadth and potency of an HIV-1-neutralizing human single-chain antibody by random mutagenesis and sequential antigen panning. 1465 51

Malignant pleural effusion (PE) is one of the poor prognostic factors in non-small cell lung cancer (NSCLC), and the detailed mechanism of the malignant PE formation is not fully elucidated. Recently, CXCR4, a receptor for chemokine stromal-derived factor-1alpha (SDF-1alpha) that can induce chemotaxis of cells, was reported to be expressed on NSCLC. In this study, we hypothesized that the SDF-1alpha/CXCR4 axis may be involved in the dissemination of malignant cells into pleural space, and investigated its expression, function, and signaling pathway using NSCLC cell lines and clinical samples from 43 patients with NSCLC with malignant PE. We found functional expression of CXCR4 on NSCLC cell lines, and also found that SDF-1alpha could induce migration via phosphatidylinositol 3 (PI-3) kinase- and p44/42 mitogen-activated protein kinase-dependent manner. The SDF-1alpha levels in malignant PE were significantly higher than those in transudate PE and showed a significant positive correlation with PE volumes. The sensitivity and specificity for prediction of recurrence of malignant PE was 61.5% and 83.3%, respectively (cutoff SDF-1alpha = 2,500 ng/ml), and better than those using pH of PE. Cancer cells in malignant PE expressed CXCR4, and mesothelial cells of the pleura stained positive for SDF-1alpha. The SDF-1alpha/CXCR4 axis is involved in the dissemination of NSCLC cells into pleural space.
Am J Respir Cell Mol Biol 2004 May
PMID:Stromal-derived factor-1alpha/CXCL12-CXCR 4 axis is involved in the dissemination of NSCLC cells into pleural space. 1869 64

The stromal cell-derived factor-1 (SDF-1)/CXCR4 system is implicated in various instances of cell migration in mammals, including the migration of lymphocytes and the formation of metastases. We have recently synthesized a potent novel CXCR4 antagonist, TN14003. The purpose of this study was to investigate the role of SDF-1/CXCR4 axis in the pancreatic cancer metastasis via cell migration and invasion, and the inhibitory effect of TN14003 on pancreatic cancer cell metastasis. The expression of CXCR4 was detected in six pancreatic cancer cell lines by Western blotting and immunocytochemistry. In migration and invasion assays, SDF-1 stimulated both migration and invasion of cancer cells in a dose-dependent manner. The maximal effect of SDF-1 was observed at 100 ng/ml. SDF-1-induced migration and invasion of cancer cells were completely blocked by 100 nM TN14003. The stimulatory effect of SDF-1 on cancer migration and the inhibitory effect of TN14003 were mediated via the alteration in phosphorylation of mitogen-activated protein kinases. Treatment of cancer cells with 100 ng/ml SDF-1 resulted in a significant increase of actin polymerization, which was reduced by 100 nM TN14003. SDF-1 enhanced cancer cell adhesion to laminin, which was not reversed by TN14003. Taken together, SDF-1/CXCR4 axis is involved in pancreatic cancer metastasis through migration and invasion. The small molecule antagonists against CXCR4 such as TN14003 might be an effective anti-metastatic agent for pancreatic cancer.
Mol Cancer Ther 2004 Jan
PMID:CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer. 1474 73

Several reports imply that bone marrow hematopoietic stem cells transdifferentiate into tissue-specific stem cells; however, the possibility of committed tissue-specific stem cells pre-existing in the bone marrow has not been dealt with adequately. We present here an alternative explanation of the so-called phenomenon of stem cell transdifferentiation. First, we postulate that tissue-committed stem/progenitor cells circulate in the peripheral blood and compete for tissue-specific niches. The circulation of these cells plays an important physiological role in maintaining a pool of stem cells in distant parts of the body and the number of these cells in peripheral blood can be increased by the administration of agents similar to those used for mobilization of hematopoietic stem cells. Second, we postulate that bone marrow tissue is a source of various stem-cell chemoattractants and survival factors and provides an environment that chemoattracts tissue-specific circulating stem/progenitor cells. In this context, we envision bone marrow as a "home" or "hide-out place" not only of hematopoietic stem cells but also of already differentiated circulating tissue-specific stem/progenitors. In support of this concept, we report here that mRNA of several early markers for muscle (Myf-5, Myo-D), neural (GFAP, nestin) and liver (CK19, fetoprotein) is detectable in circulating (adherent cell-depleted) peripheral blood mononuclear cells. Moreover, using real-time RT-PCR, we found that the level of expression of these markers increases in the peripheral blood of humans and mice after mobilization by G-CSF. Furthermore, using stromal-derived factor-1 (SDF-1) chemotaxis and real-time RT-PCR analysis, we present evidence that early tissue-specific stem cells reside in normal human and murine bone marrow, express the CXCR4 receptor on their surface and can be highly enriched (in humans and mice) after chemotaxis to SDF-1 gradient. All our experiments were performed on freshly isolated cells to exclude the potential contribution of transdifferentiated hematopoietic stem or mesenchymal cells in the culture. We maintain that any transdifferentiation studies employing populations of bone marrow cells should rule out the possibility that the apparently pure hematopoietic stem cell population could in fact contain pre-existing tissue-specific stem/progenitors.
Blood Cells Mol Dis
PMID:Tissue-specific muscle, neural and liver stem/progenitor cells reside in the bone marrow, respond to an SDF-1 gradient and are mobilized into peripheral blood during stress and tissue injury. 1475 13

Agonist-stimulated internalization followed by recycling to the cell membrane play an important role in fine-tuning the activity of chemokine receptors. Because the recycling of chemokine receptors is critical for the reestablishment of the cellular responsiveness to ligand, it is crucial to understand the mechanisms underlying the receptor recycling and resensitization. In the present study, we have demonstrated that the chemokine receptor CXCR2 associated with myosin Vb and Rab11-family interacting protein 2 (FIP2) in a ligand-dependent manner. Truncation of the C-terminal domain of the receptor did not affect the association, suggesting that the interactions occur upstream of the C terminus of CXCR2. After ligand stimulation, the internalized CXCR2 colocalized with myosin Vb and Rab11-FIP2 in Rab11a-positive vesicles. The colocalization lasted for approximately 2 h, and little colocalization was observed after 4 h of ligand stimulation. CXCR2 also colocalized with myosin Vb tail or Rab11-FIP2 (129-512), the N-terminal-truncated mutants of myosin Vb and Rab11-FIP2, respectively, but in a highly condensed manner. Expression of the enhanced green fluorescent protein-tagged myosin Vb tail significantly retarded the recycling and resensitization of CXCR2. CXCR2 recycling was also reduced by the expression Rab11-FIP2 (129-512). Moreover, expression of the myosin Vb tail reduced CXCR2- and CXCR4-mediated chemotaxis. These data indicate that Rab11-FIP2 and myosin Vb regulate CXCR2 recycling and receptor-mediated chemotaxis and that passage of internalized CXCR2 through Rab11a-positive recycling system is critical for physiological response to a chemokine.
Mol Biol Cell 2004 May
PMID:Rab11-family interacting protein 2 and myosin Vb are required for CXCR2 recycling and receptor-mediated chemotaxis. 1500 34

To clarify the relationship between the amino acid variations of the gp120 of human immunodeficiency virus type 1 (HIV-1) and the chemokine receptors that are used as the second receptor for HIV, we evaluated amino acid site variation of gp120 between the X4 strains (use CXCR4) and the R5 strains (use CCR5) from 21 sequences of subtype B. Our analysis showed that residues 306 and 322 in the V3 loop and residue 440 in the C4 region were associated with usage of the second receptor. The polymorphism at residue 440 is clearly associated with the usage of the second receptor: The amino acid at position 440 was a basic amino acid in the R5 strains, and a nonbasic and smaller amino acid in the X4 strains, while the V3 loop of the X4 strains was more basic than that of the R5 strains. This suggests that residue 440 in the C4 region, which is close to the V3 loop in the three-dimensional structure, is critical in determining which second receptor is used. Analysis of codon frequency suggests that, in almost all cases, the difference at residue 440 between basic amino acids in the R5 strains and nonbasic amino acids in the X4 strains could be due to a single nucleotide change. These findings predict that the evolutionary changes in amino acid residue 440 may be correlated with evolutionary changes in the V3 loop. One possibility is that a change in electric charge at residue 440 compensates for a change in electric charge in the V3 loop. The amino acid polymorphism at position 440 can be useful to predict the cell tropism of a strain of HIV-1 subtype B.
J Mol Evol 2004 Mar
PMID:Linkage of amino acid variation and evolution of human immunodeficiency virus type 1 gp120 envelope glycoprotein (subtype B) with usage of the second receptor. 1504 88

Metastatic renal cell carcinoma (RCC) is often resistant to standard treatment, thereby requiring new therapeutic strategies. In this regard, tumor cell migration and metastasis have recently been shown to be regulated by chemokines and their respective receptors (e.g., SDF-1alpha/CXCR4). In the context of RCC, up-regulation of CXCR4 expression is closely related to the development of invasive cancer. Thus, we hypothesized that the CXCR4 pathway could be exploited for RCC targeting with gene therapy vectors. In this regard, targeting adenoviral vectors to tumor cells is critically dependent on tumor-specific gene expression. Toward the end of RCC tumor targeting, we evaluated the utility of the CXCR4 promoter in an adenoviral context. First, overexpression of CXCR4 was confirmed in several RCC cell lines. Next, an adenoviral vector was constructed, whereby the human CXCR4 promoter drives the expression of a reporter gene. We tested the activity of the CXCR4 promoter in vitro and in vivo in relevant models. Our data indicate that the human CXCR4 promoter is highly active in RCC cells but not in normal human cells. Finally, biodistribution studies in mice demonstrated dramatic repression of the CXCR4 promoter in the liver but not in the kidney. In conclusion, the unique activity of the CXCR4 promoter in RCC lines and its repression in normal human cells and in the murine liver underscore its potential utility as a novel candidate for transcriptional targeting of RCC.
Mol Cancer Ther 2004 Jun
PMID:Transcriptional targeting in renal cancer cell lines via the human CXCR4 promoter. 1521 Aug 54


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