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

Chemokines are small secreted proteins with chemoattractant properties for immune cells. Besides their role in the immune system, chemokines and their receptors may play important roles in the central nervous system. Neurodegenerative disorders that involve neuroinflammation such as multiple sclerosis, stroke, Alzheimer's disease, Parkinson's disease and HIV-associated dementia are commonly associated with local upregulation and release of chemokines. However, recent work has established that certain chemokines, constitutively expressed in the brain, exert functions in the brain that are distinct from inflammation. These chemokines regulate neuronal migration during brain development, modulate neuronal activity and play a role in various neurodegenerative diseases, pain and more recently in neuroendocrine functions. All these novel aspects, mainly focused on the chemokine stromal cell-derived factor-1/CXCL12 and its receptor CXCR4, were presented by pioneers in the field during the symposium held at the sixth International Congress of Neuroendocrinology in Pittsburgh, Pennsylvania, USA in June 2006.
J Mol Endocrinol 2007 Mar
PMID:Chemokines as modulators of neuroendocrine functions. 1733 97

The chemokine SDF-1alpha and its cognate receptor CXCR4 are expressed in several neuronal populations. This review focuses on our current knowledge about the actions of this chemokine on neuronal excitability, through CXCR4 or other yet unknown pathways. In various neuronal populations (CA1 neurons of the hippocampus, granular and Purkinje cells of the cerebellum, melanin-concentrating hormone neurons of the lateral hypothalamus, vasopressinergic neurons of the supraoptic and the paraventricular nucleus of the hypothalamus, and dopaminergic neurons of the substantia nigra), SDF-1alpha can modulate the activity of neurons by multiple regulatory pathways including and often combining: (i) modulation of voltage-dependent channels (sodium, potassium, and calcium), (ii) activation of the G-protein-activated inward rectifier potassium current, and (iii) increase in neurotransmitter release (gamma-amino butyric acid (GABA), glutamate, and dopamine), often through Ca-dependent mechanisms. The possible mechanisms underlying these effects and their consequences in terms of modulation of neuroendocrine systems and physiopathology are discussed.
J Mol Endocrinol 2007 Mar
PMID:Multiple actions of the chemokine stromal cell-derived factor-1alpha on neuronal activity. 1733 99

Chemotactic cytokines (chemokines) are small secreted proteins that control leukocyte trafficking in immune organs. Chemokines which are induced in the brain during conditions of inflammation play a role in the local immune response. Recently, it has been established in the rodent brain that distinct chemokines and chemokine receptors are constitutively expressed by neurons and that these chemokines modulate neuronal functions. The CXC motif chemokine stromal cell-derived factor-1 (SDF-1), CXCL12 together with its cognate receptor CXCR4 represents the best-characterized neuronal chemokine system. Transwell migration assays with neuronal precursors, pharmacological manipulation of CXCR4 signaling in embryonic brain explants, and histochemical studies of SDF-1- or CXCR4-deficient mouse embryos provide proof that SDF-1 directs neuronal migration and axonal pathfinding in the developing nervous system. In the adult brain, SDF-1 is thought to influence neurogenesis as well as recruitment of brain resident and non-resident circulating cells toward sites of lesion. The present review summarizes patterns and functions of the SDF-1/CXCR4 system in the rodent brain with a focus on the developing and adult cerebral cortex.
J Mol Endocrinol 2007 Mar
PMID:CXC chemokine receptor 4 regulates neuronal migration and axonal pathfinding in the developing nervous system: implications for neuronal regeneration in the adult brain. 1733

Chemokines are key factors involved in the regulation of immune response, through the activation and control of leukocyte traffic, lymphopoiesis and immune surveillance. However, a large number of chemokines and their receptors are expressed in central nervous system (CNS) cells, either constitutively or induced by inflammatory stimuli, playing a role in many neuropathological processes. Stromal cell-derived factor 1 (SDF1) is a chemokine whose extra-immunological localization and functions have been extensively studied. SDF1 and its receptor CXCR4 were identified in both neurons and glia of many brain areas, including the hypothalamus, as well as at the pituitary level. Importantly, SDF1 and CXCR4 expression is increased in brain tumors in which their activity induced tumor cell proliferation and brain parenchyma invasion. Despite their localization, to date very few reports addressed the role of CXCR4 and SDF1 in the modulation of the hypothalamus/pituitary axis and their possible involvement in the development of pituitary adenomas. In this review, we discuss previous literature data on the role of chemokines in normal and adenomatous pituitary cells, focusing on recent data from our group showing that CXCR4 activation controls proliferation and both prolactin and GH release in the pituitary adenoma cell line GH4C1 through a complex network of intracellular signals. Thus, the SDF1/CXCR4 system together with other chemokinergic ligand-receptor pairs, may represent a novel regulatory pathway for pituitary function and, possibly, be involved in pituitary adenoma development. These lines of evidence suggest that the inhibition of chemokine receptors may represent a novel pharmacological target for the treatment of pituitary adenomas.
J Mol Endocrinol 2007 Mar
PMID:Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior pituitary function. 1733 1

Stromal cell-derived factor-1alpha (SDF-1alpha) is a CXC chemokine that interacts with CXCR4 receptor. Tac1 encodes peptides belonging to the tachykinins, including substance P. SDF-1alpha production is decreased in Tac1 knockdown breast cancer cells and is also reduced in these cancer cells following contact with bone marrow stroma when Tac1 expression is increased. Here, we report on the effects of relatively high and low SDF-1alpha levels on Tac1 expression in nontumorigenic breast cells MCF12A. Reporter gene assays, Northern analyses, and ELISA for substance P showed increased Tac1 expression at 20 and 50 ng/mL SDF-1alpha and reduced expression at 100 ng/mL. Omission of the untranslated region showed a dose-dependent effect of SDF-1alpha on reporter gene activity, suggesting that receptor desensitization cannot account for the suppressive effects at 100 ng/mL SDF-1alpha. Tac1 expression at high SDF-1alpha involves an intracellular signaling pathway that incorporates the activation of phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-AKT-nuclear factor-kappaB (NF-kappaB). The major repressive effect occurs via NF-kappaB located within exon 1. In summary, NF-kappaB is involved in the repression of Tac1 at higher levels of SDF-1alpha in MCF12A. These results are relevant to dysfunction of Tac1 in breast cancer cells and also provide insights on the behavior of breast cancer cells as they traverse across gradient changes of SDF-1alpha.
Mol Cancer Res 2007 Apr
PMID:Nuclear factor-kappaB accounts for the repressor effects of high stromal cell-derived factor-1alpha levels on Tac1 expression in nontumorigenic breast cells. 1740 18

Stromal cell-derived factor-1 (SDF-1) participates in mobilizing bone marrow-derived stem cells, via its receptor CXCR4. We studied the role of the SDF-1/CXCR4 axis in a rodent model of bleomycin-induced lung injury in C57BL/6 wild-type and matrix metalloproteinase (MMP)-9 knockout mice. After intratracheal instillation of bleomycin, SDF-1 levels in serum and bronchial alveolar lavage fluid increased. These changes were accompanied by increased numbers of CXCR4(+) cells in the lung and a decrease in a population of CXCR4(+) cells in the bone marrow that did not occur in MMP-9(-)/(-) mice. Both SDF-1 and lung lysates from bleomycin-treated mice induced migration of bone marrow-derived stem cells in vitro that was blocked by a CXCR4 antagonist, TN14003. Treatment of mice with TN14003 with bleomycin-induced lung injury significantly attenuated lung fibrosis. Lung tissue from patients with idiopathic pulmonary fibrosis had higher numbers of cells expressing both SDF-1 and CXCR4 than did normal lungs. Our data suggest that the SDF-1/CXCR4 axis is important in the complex sequence of events triggered by bleomycin exposure that eventuates in lung repair. SDF-1 participates in mobilizing bone marrow-derived stem cells, via its receptor CXCR4.
Am J Respir Cell Mol Biol 2007 Sep
PMID:Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. 1746 94

The production of chemokine stromal cell-derived factor (SDF)-1 is significantly higher in synovial fluid of patients with osteoarthritis and rheumatoid arthritis. Matrix metalloproteinase (MMP)-13 may contribute to the breakdown of articular cartilage during arthritis. Here, we found that SDF-1alpha increased the secretion of MMP-13 in cultured human chondrocytes, as shown by reverse transcriptase-polymerase chain reaction, Western blot, and zymographic analysis. SDF-1alpha also increased the surface expression of CXCR4 receptor in human chondrocytes. CXCR4-neutralizing antibody, CXCR4-specific inhibitor [1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane (AMD3100)], or small interfering RNA against CXCR4 inhibited the SDF-1alpha-induced increase of MMP-13 expression. The transcriptional regulation of MMP-13 by SDF-1alpha was mediated by phosphorylation of extracellular signal-regulated kinases (ERK) and activation of the activator protein (AP)-1 components of c-Fos and c-Jun. The binding of c-Fos and c-Jun to the activator protein (AP-1) element on the MMP-13 promoter and the increase in luciferase activity was enhanced by SDF-1alpha. Cotransfection with dominant-negative mutant of ERK2 or c-Fos and c-Jun antisense oligonucleotide inhibited the potentiating action of SDF-1alpha on MMP-13 promoter activity. Taken together, our results provide evidence that SDF-1alpha acts through CXCR4 to activate ERK and the downstream transcription factors (c-Fos and c-Jun), resulting in the activation of AP-1 on the MMP-13 promoter and contributing cartilage destruction during arthritis.
Mol Pharmacol 2007 Sep
PMID:Stromal cell-derived factor-1 induces matrix metalloprotease-13 expression in human chondrocytes. 1755 Sep 83

We have previously shown that a stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system is involved in the establishment of lymph node metastasis, but not in that of distant metastasis, in oral squamous cell carcinoma (SCC). In this study, we investigated the role of the autocrine SDF-1/CXCR4 system, with a focus on distant metastasis in oral SCC cells. The immunohistochemical staining of SDF-1 and CXCR4 using primary oral SCCs and metastatic lymph nodes showed a significantly higher number of SDF-1-positive cases among the metastatic lymph nodes than among the primary oral SCCs, which was associated with a poor survival rate among those of the former group. The forced expression of SDF-1 in B88 cells, which exhibit functional CXCR4 and lymph node metastatic potential (i.e., the autocrine SDF-1/CXCR4 system), conferred enhanced cell motility and anchorage-independent growth potential onto the cells. Orthotopic inoculation of the transfectant into nude mice was associated with an increase in the number of metastatic lymph nodes and more aggressive metastatic foci in the lymph nodes. Furthermore, the SDF-1 transfectant (i.e., the autocrine SDF-1/CXCR4 system) exhibited dramatic metastasis to the lung after i.v. inoculation, whereas the mock transfectant (i.e., the paracrine SDF-1/CXCR4 system) did not. Under the present conditions, AMD3100, a CXCR4 antagonist, significantly inhibited the lung metastasis of the SDF-1 transfectant, ameliorated body weight loss, and improved the survival rate of tumor-bearing nude mice. These results suggested that, in cases of oral SCC, the paracrine SDF-1/CXCR4 system potentiates lymph node metastasis, but distant metastasis might require the autocrine SDF-1/CXCR4 system.
Mol Cancer Res 2007 Jul
PMID:Involvement of an autocrine stromal cell derived factor-1/CXCR4 system on the distant metastasis of human oral squamous cell carcinoma. 1763 24

Hepatocyte growth factor (HGF), a cytokine of tumor microenvironment, exerts opposite effects on CXCR4 expression in MCF-7 (low invasive) and MDA-MB231 (highly invasive) breast carcinoma cells, and here, we show that completely different molecular mechanisms downstream of c-Src activation were involved. As experimental models, we used cells transfected with two CXCR4 promoter constructs and treated with HGF or cotransfected with c-Src wild-type (Srcwt) expression vector; phospho-c-Src formation was enhanced in both cell lines. In MCF-7 cells, consistent with activations of CXCR4Luc constructs after HGF treatment and Srcwt expression, Ets1 and nuclear factor-kappaB (NF-kappaB) transcription factors were activated. In contrast, in MDA-MB231 cells, CXCR4Luc construct, Ets1 and NF-kappaB activities decreased. The divergence point seemed to be downstream of HGF/c-Src and consisted in the interaction between c-Src and the substrate histone deacetylase 3 (HDAC3). Only in MDA-MB231 cells, HDAC3 level was enhanced in membranes and nuclei 30 min after HGF and colocalized/coimmunoprecipitated with phospho-c-Src and phosphotyrosine. Thus, the CXCR4 induction by HGF in MCF-7 cells required NF-kappaB and Ets1 activations, downstream of phosphoinositide-3-kinase/Akt, whereas in HGF-treated MDA-MB231 cells, HDAC3 activation via c-Src probably caused a reduction of transcription factor activities, such as that of NF-kappaB. These results indicate possible roles of HGF in invasive growth of breast carcinomas. By enhancing CXCR4 in low invasive tumor cells, HGF probably favors their homing to secondary sites, whereas by suppressing CXCR4 in highly invasive cells, HGF might participate to retain them in the metastatic sites.
Mol Cancer Res 2007 Aug
PMID:c-Src/histone deacetylase 3 interaction is crucial for hepatocyte growth factor dependent decrease of CXCR4 expression in highly invasive breast tumor cells. 1769 9

CXCR4, the primary receptor for CXCL12, plays a critical role in the development of hematopoietic, vascular, central nervous, and immune systems by mediating directional migration of precursor cells. This mechanism promotes homing of tumor cells to metastatic sites that secrete CXCL12, and CXCR4 expression is a negative prognostic factor in acute myelogenous leukemia (AML). To elucidate mechanisms that regulate CXCR4 signaling, we used a proteomic approach to identify proteins physically associated with CXCR4. Analysis of CXCR4 immune complexes identified nucleophosmin (NPM), which was confirmed by reciprocal coimmunoprecipitation for NPM. Constitutively active CXCR4 variants bound higher levels of NPM than the wild-type receptor, which was reversed by T140, an inverse agonist. NPM binding to CXCR4 localized interactions to the C terminus and cytoplasmic loop (CL)-3, but not CL-1 or CL-2. Alanine scanning mutagenesis demonstrated that positively charged amino acids in CL-3 were critical for NPM binding. Recombinant NPM decreased GTP binding in membrane fractions after activation of CXCR4 by CXCL12. Suppression of NPM expression enhanced chemotactic responses to CXCL12, and, conversely, overexpression of a cytosolic NPM mutant reduced chemotaxis induced by CXCL12. This study provides evidence for a novel role for NPM as a negative regulator of CXCR4 signaling induced by CXCL12 that may be relevant to the biology of AML.
Mol Pharmacol 2007 Nov
PMID:Association of nucleophosmin negatively regulates CXCR4-mediated G protein activation and chemotaxis. 1771 99


<< Previous 1 2 3 4 5 6 7 8 9 10