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

The stromal cell-derived factor-1 (SDF-1) gene contains a common polymorphism, termed SDF1-3'A, in an evolutionarily conserved segment of the 3'-untranslated region (3'-UTR). We compared SDF-1 genotypes in patients diagnosed with lymphoid leukemias and lymphomas. Since the SDF1-3'A variant deletes the MspI restriction site, PCR-restriction fragment length polymorphism (RFLP) analysis was used for identification of genotypes. We identified the heterozygous genotype (3'A/wt) in 38.8% (24/62) of lymphoma patients and in 26.2% (11/42) of lymphoid leukemias. The percentage of 3'A carriers was significantly higher in lymphomas (43.5%) than in lymphoid leukemias (26.2%; P < 0.05). Our study indicates that lymphoma patients from Brazil are more likely to carry the 3'A gene than patients with lymphoid leukemias, suggesting that this polymorphism may be a differential determinant of lymphomas and lymphoid leukemia.
Blood Cells Mol Dis
PMID:Molecular investigation of the stromal cell-derived factor-1 chemokine in lymphoid leukemia and lymphoma patients from Brazil. 1522 17

In this study, we have characterized the signaling pathways mediated by CXCR4 in breast cancer cells and its role in breast cancer cell invasion and migration. Stromal cell-derived factor 1alpha (SDF-1alpha; CXCL12) stimulation of breast cancer cells resulted in phosphoinositide 3-kinase (PI-3K) activation, AKT phosphorylation, and activation of the FKHRL1 transcription factor. In addition, SDF-1alpha induced activation of the focal adhesion kinase (FAK) as well as the migration of breast cancer cells. Expression of SDF-1alpha, the ligand of CXCR4, was about 2-fold higher in microdissected human breast epithelial cancer cells as compared with normal epithelial cells. Immunohistochemical analysis indicated that SDF-1alpha expression is consistently higher in primary breast tumor cells than in normal breast epithelial cells. Furthermore, SDF-1alpha induced blood vessel instability, through increased vascular permeability, resulting in the penetration of breast tumor cells through the human brain microvascular endothelial cells (HBMEC). Notably, the migration of breast cancer cells was inhibited by the PI-3K inhibitor, Wortmannin, and the Ca(2+) inhibitor BAPTA/AM, indicating that transendothelial breast cancer cell migration induced by SDF-1alpha is mediated by activation of the PI-3K/AKT pathway and Ca(2+)-mediated signaling. Blockade of the CXCR4/SDF1 signaling pathway with anti-CXCR4 antibody also decreased transendothelial breast cancer cell migration as well as vascular permeability. This study focuses on novel interactions between highly relevant signaling pathways in breast cancer cells and brain microvascular endothelial cells and may provide insights into the molecular mechanisms of CXCR4/SDF-1alpha-mediated breast cancer metastasis to the brain.
Mol Cancer Res 2004 Jun
PMID:Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. 1523 8

Mouse platelet basic protein (CXCL7/mPBP) was cloned from thymic stromal cells and further identification indicated that it was expressed in thymic monocytes/macrophages (Mo/Mphis). Recombinant mPBP was chemoattractive for target cells of polymorphonuclear leucocytes, peritoneal Mo/Mphis and splenic lymphocytes with distinct potencies. CXCR2 was identified to be a cognate receptor for mPBP. Mouse thymocyte subsets of CD4-CD8- double-negative (DN), CD4+CD8+ double-positive (DP), CD4+CD8- single-positive (CD4SP) and CD4-CD8+ single-positive (CD8SP) expressed cell surface CXCR2 with different positive percentages and expression levels. mPBP was chemoattractive for thymocyte subsets with the potency order DN>DP> CD8SP>CD4SP, consistent with the levels of CXCR2 expressed on the respective cells. Thus, mPBP in thymus is functionally redundant with chemokine CXCL12/ SDF-1. Moreover, our finding that thymic Mo/Mphis can produce mPBP implies that they may have other functions apart from acting as scavengers in thymus.
Cell Mol Life Sci 2004 Aug
PMID:Differential chemotactic potential of mouse platelet basic protein for thymocyte subsets. 1528 35

Stromal cell-derived factor-1 (SDF-1 or CXCL12) is the physiologic ligand for the chemokine receptor CXCR4. CXCR4-mediated signalling regulates cell migration and apoptosis in certain haematopoietic and neuronal cells. Using gene profiling, we determined that CXCR4 is the only chemokine receptor for which mRNA expression is regulated during trophoblast differentiation in vitro. Based on the known effects of CXCR4 ligation, we hypothesized that CXCR4 activation may regulate placental trophoblast cell survival (i.e. protection from apoptosis), an important mechanism for the establishment and maintenance of the uteroplacental barrier. Human cytotrophoblasts (CTBs) were cultured in defined media and treated with graded doses of SDF-1 (10-100 ng/ml) or with an anti-CXCR4 neutralizing antibody. Exposure to anti-CXCR4 antibody reduced CTB cell numbers by 25-40%. Treatment with SDF-1 decreased the proportions of apoptotic terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick-end labelling(+) cells (apoptotic index [AI] of 2.79+/-0.61% [control] versus 1.88+/-0.56% [SDF-1]; P<0.05) and caspase-activated cells (AI of 7.95+/-2.49% [control] versus 3.81+/-1.49% [SDF-1]; P<0.05). We determined that SDF-1 also activated the triple MAP Kinase isoforms ERK1/2 and p38 in trophoblasts. Immunocytochemistry confirmed SDF-1-induced nuclear translocation of phosphorylated ERK1/2. Blocking of ERK1/2 signalling with the specific inhibitor PD98059 reversed SDF-1-mediated inhibition of apoptosis (AI of 1.65+/-0.34 [SDF-1] versus 3.50+/-0.5 [SDF-1 + PD98059]; P<0.05), suggesting that SDF-1 acts through this pathway as a trophoblast survival factor. These results indicate that SDF-1/CXCR4 signalling stimulates anti-apoptotic pathways in cultured trophoblasts. This chemotactic ligand/receptor system may promote trophoblast survival during pregnancy. Alterations in SDF-1 and/or CXCR4 expression or function may be associated with specific pregnancy disorders.
Mol Hum Reprod 2004 Dec
PMID:Stromal cell-derived factor-1 (SDF-1) signalling regulates human placental trophoblast cell survival. 1547 70

Estrogen receptor alpha (ERalpha) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ERalpha activity and has been used in breast cancer therapy. Tamoxifen-bound ERalpha associates with nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) at certain target genes. Here we show the effects of reducing N-CoR and SMRT levels on the actions of estrogen and tamoxifen in breast cancer cells. Silencing both corepressors led to tamoxifen-stimulated cell cycle progression without activation of the ERalpha target genes c-myc, cyclin D1, or stromal cell-derived factor 1, which play a role in estrogen-induced proliferation. By contrast, expression of X-box binding protein 1 was markedly elevated in tamoxifen-treated cells in which N-CoR and SMRT had been silenced. The gain in cell cycle entry seen with tamoxifen when N-CoR and SMRT were silenced was dependent on ERalpha and not observed upon treatment with estradiol or epidermal growth factor. These results suggest that N-CoR and SMRT play an active role in preventing tamoxifen from stimulating proliferation in breast cancer cells through repression of a subset of target genes involved in ERalpha function and cell proliferation.
Mol Endocrinol 2005 Jun
PMID:Cell cycle progression stimulated by tamoxifen-bound estrogen receptor-alpha and promoter-specific effects in breast cancer cells deficient in N-CoR and SMRT. 1580 75

Emerging evidence shows that the stromal cell-derived factor 1 (SDF-1)/CXCR4 interaction regulates multiple cell signaling pathways and a variety of cellular functions such as cell migration, proliferation, and survival. There is little information linking the cellular functions and individual signaling pathways mediated by SDF-1 and CXCR4 in human cancer cells. In this study, we have shown that human epitheloid carcinoma HeLa cells express functional CXCR4 by reverse transcription-PCR, immunofluorescent staining, and 125I-SDF-1alpha ligand binding analyses. The treatment of HeLa cells with recombinant SDF-1alpha results in time-dependent Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) activations. The SDF-1alpha-induced Akt and ERK1/2 activations are CXCR4 dependent as confirmed by their total inhibition by T134, a CXCR4-specific peptide antagonist. Cell signaling analysis with pathway-specific inhibitors reveals that SDF-1alpha-induced Akt activation is not required for ERK1/2 activation and vice versa, indicating that activations of Akt and ERK1/2 occur independently. Functional analysis shows that SDF-1alpha induces a CXCR4-dependent migration of HeLa cells. The migration can be totally blocked by phosphoinositide 3-kinase inhibitors, wortmannin or LY294002, whereas mitogen-activated protein/ERK kinase inhibitors, PD98059 and U0126, have no significant effect on SDF-1alpha-induced migration, suggesting that Akt activation, but not ERK1/2 activation, is required for SDF-1alpha-induced migration of epitheloid carcinoma cells.
Mol Cancer Res 2005 Apr
PMID:Akt activation, but not extracellular signal-regulated kinase activation, is required for SDF-1alpha/CXCR4-mediated migration of epitheloid carcinoma cells. 1583 76

It has been suggested that SDF1-G801A, a single nucleotide polymorphism (SNP) in the 3' untranslated region (UTR) of the SDF1 gene, is associated with susceptibility to diseases such as AIDS and type-I diabetes. However, experimental studies examining the effect of SDF1-G801A on SDF-1 expression have not supported its functional importance. In this study, to examine whether other polymorphisms have a cis-acting effect on SDF1 expression, we carried out haplotype analyses of the SDF1 gene and the allele-specific transcript quantification utilizing Epstein-Barr virus-transformed lymphoblastoid cell lines with heterozygous genotype for SDF1-G801A. Haplotype-based analyses on the proportion of the allele-specific transcripts revealed the presence of haplotypes associated with a decreased amount of the transcripts. In addition, we observed haplotypic variation in response to dibutyl cyclic AMP and tetradecanoyl phorbol acetate that enhances the levels of SDF-1 transcripts probably through activation of transcription factors. Showing evidence that polymorphisms other than the SDF1-G801A have a cis-acting effect on expression of SDF-1 transcripts, the results of this study contribute to the interpretation of previous disease-association studies and to the selection of SNP markers for future studies. As shown in this study, allele-specific transcript quantification coupled with haplotype analyses can be an effective tool for detecting cis-acting polymorphisms in expressional regulation.
Hum Mol Genet 2005 Jun 15
PMID:Allele-specific transcript quantification detects haplotypic variation in the levels of the SDF-1 transcripts. 1584 97

The chemokine CXCL12 promotes T lymphocyte adhesion mediated by the integrin alpha4beta1. CXCL12 activates the GTPase Rac, as well as Vav1, a guanine-nucleotide exchange factor for Rac, concomitant with up-regulation of alpha4beta1-dependent adhesion. Inhibition of CXCL12-promoted Rac and Vav1 activation by transfection of dominant negative Rac or Vav1 forms, or by transfection of their siRNA, remarkably impaired the increase in T lymphocyte attachment to alpha4beta1 ligands in response to this chemokine. Importantly, inhibition of Vav1 expression by RNA interference resulted in a blockade of Rac activation in response to CXCL12. Adhesions in flow chambers and soluble binding assays using these transfectants indicated that initial ligand binding and adhesion strengthening mediated by alpha4beta1 were dependent on Vav1 and Rac activation by CXCL12. Finally, CXCL12-promoted T-cell transendothelial migration involving alpha4beta1-mediated adhesion was notably inhibited by expression of dominant negative Vav1 and Rac. These results indicate that activation of Vav1-Rac signaling pathway by CXCL12 represents an important inside-out event controlling efficient up-regulation of alpha4beta1-dependent T lymphocyte adhesion.
Mol Biol Cell 2005 Jul
PMID:Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1. 1587 91

Chemokines are best known for their vital role in leukocyte chemotaxis, as part of the larger inflammatory response. Expression analysis and functional characterization of chemokines in mammalian species have often overlooked the role of these proteins under homeostatic conditions. Recent investigations of chemokine diversity in teleost fish have also centered on the immune-related functions of chemotactic cytokines, such as CXCL8 and CXCL10. While a disease-based approach to chemokines is essential to the development of remediative therapies for both human and animal infections, it may be a poor measure of the overall complexity of chemokine functions. As part of a larger effort to assess the conservation of chemokine diversity in teleost fish, we report here the identification of three novel, constitutively expressed CXC chemokines from channel catfish (Ictalurus punctatus). Phylogenetic analyses indicated that two of the three CXC chemokines were orthologues for mammalian CXCL12 and CXCL14, respectively. Whereas a clear orthology could not yet be established for the third CXC chemokine, it shared highest amino acid identity with mammalian CXCL2. All three CXC chemokines show expression in a wide range of tissues, and early expression during development was observed for CXCL12. The expression of this new set of catfish CXC chemokines was not induced during challenge by infection of Edwardsiella ictaluri, the causative agent of the fish pathogen enteric septicemia of catfish. In contrast to the gene duplication of CXCL12 in carp and zebrafish, Southern blot analysis indicated that all three catfish CXC chemokines exist as single copy genes in the catfish genome suggesting that gene duplication of CXC chemokines in specific teleost fish was a recent evolutionary event.
Mol Immunol 2005 Jul
PMID:Constitutive expression of three novel catfish CXC chemokines: homeostatic chemokines in teleost fish. 1595 Jul 31

Myocardial infarction leads to scar formation and subsequent reduced cardiac performance. The ultimate therapy after myocardial infarction would pursue stem cell-based regeneration. The aim of stem cell-mediated cardiac repair embodies restoration of cardiac function by regeneration of healthy myocardial tissue, which is accomplished by neo-angiogenesis and cardiogenesis. A major reservoir of adult autologous stem cells distal from the heart is the bone marrow. Adequate regulation of signaling between the bone marrow, the peripheral circulation and the infarcted myocardium is important in orchestrating the process of mobilization, homing, incorporation, survival, proliferation and differentiation of stem cells, that leads to myocardial regeneration. In this review, we discuss key signaling factors, including cytokines, chemokines and growth factors, which are involved in orchestrating the stem cell driven repair process. We focus on signaling factors known for their mobilizing and chemotactic abilities (SDF-1, G-CSF, SCF, IL-8, VEGF), signaling factors that are expressed after myocardial infarction involved in the patho-physiological healing process (TNF-alpha, IL-8, IL-10, HIF-1alpha, VEGF, G-CSF) and signaling factors that are involved in cardiogenesis and neo-angiogenesis (VEGF, EPO, TGF-beta, HGF, HIF-1alpha, IL-8). The future therapeutic application and capacity of secreted factors to modulate tissue repair after myocardial infarction relies on the intrinsic potency of factors and on the optimal localization and timing of a combination of signaling factors to stimulate stem cells in their niche to regenerate the infarcted heart.
J Mol Cell Cardiol 2005 Aug
PMID:Signaling factors in stem cell-mediated repair of infarcted myocardium. 1599 20


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