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

Activated mast cells release stored and newly synthesized mediators that influence the caliber and responsiveness of inflamed airways. In this work, we show that alloimmune-mediated mechanisms induce mast cell activation and expression of CC chemokines in remodeling rat tracheal allografts. Decreased expression of rat mast cell protease (RMCP) I and II, in concert with tryptase release in tracheal allografts, identified degranulation of stored serine proteases as an early mast cell response to allotransplantation. Transient upregulation of c-Kit expression occurred in a synchronous manner, suggesting that c-Kit receptor signaling controls mast cell responses. Increased expression of CC chemokine ligand (CCL) 2 and CCL3 by RMCP I-positive cells identified mast cells as epithelial and mesenchymal sources of chemoattractant chemokines in allograft airways. Cyclosporin A immunosuppression both attenuated and delayed these changes in mast cell phenotypes. Incubation of rat basophil leukemia 2H3 cells with CCL2 or CCL3 decreased surface c-Kit expression, an effect blocked by protease inhibitors. By controlling surface receptor availability, CC chemokines may regulate c-Kit signaling via a novel proteolytic mechanism. These data suggest that targeting alloimmune responses and restoring quiescence of mast cells may attenuate the development of fibroproliferative and obstructive distortions of bronchiolar architecture in lung allografts.
Am J Respir Cell Mol Biol 2004 Aug
PMID:Induction of mast cell activation and CC chemokine responses in remodeling tracheal allografts. 1505 85

We have used quantitative RT-PCR to analyse the mRNA expression profile of the major components of the IGF axis in different stages of murine mammary gland development, including late pregnancy, lactation and involution. We have shown that all the genes studied, IGF-I, IGF-II, IGF receptor (IGFR) and IGF-binding protein (IGFBP)-1 to -6, were expressed in every stage, albeit at greatly differing levels and displaying unique expression profiles between developmental stages. IGF-I was always expressed at significantly higher levels than either IGF-II or IGFR. This suggests that IGF-I may be the more important IGF during mammary morphogenesis. Overall, IGFBP-3 demonstrated the highest level of expression of any of the IGFBP genes throughout all the developmental stages studied. However, within developmental stages, by far the highest level of expression of any of the IGFBPs was that of IGFBP-5 at day 2 of involution; this was almost an order of magnitude higher than any of the other IGFBP levels recorded. This corroborated our previous findings that the levels of IGFBP-5 protein are highly elevated in the involuting mammary gland, and demonstrated that this up-regulation of IGFBP-5 operates at the level of transcriptional control or message stability. Comparison of the expression profile for these different genes would strongly suggest that they are likely to have differential functions throughout mammary gland development, and also highlights potential interactions and co-regulation between different members of this axis. In addition, our results have identified some similarities and differences in the expression of IGFBPs between the mouse mammary epithelial cell line, HC11, and the normal mammary gland which are worthy of study, most notably the differential regulation of IGFBP-2 and the site of expression of IGFBP-4 and -6. Overall, this study has demonstrated the importance and complexity of the IGF axis during mammary gland development and provides a valuable resource for future research in this area.
J Mol Endocrinol 2004 Aug
PMID:A quantitative RT-PCR study of the mRNA expression profile of the IGF axis during mammary gland development. 1529 53

Natural killer (NK) cells comprise a set of lymphocytes that is capable of mediating innate immune responses to viral infections, malignancies, and allogeneic bone marrow grafts. This review summarizes what is known about the mechanisms NK cells use to arrive at their sites of action. NK cells express a wide array of adhesion molecules including alphaLbeta2, alphaMbeta2, alphaXbeta2, and alpha4beta1 integrins, ICAM-1, PSGL-1, and L-selectin. Like other immune and inflammatory cells, NK cells use the blood circulation to enter tissues and organs, which requires that they interact with the vessel wall under flow conditions, arrest, and transmigrate. NK cells are able to chemotax to a variety of cytokines and chemokines, including IL-12, IFN-(alpha/beta, CCL2, 3, 4, 5, 7, 8, CXCL8, and CX3CL1. In many cases, NK cells appear to migrate towards these soluble factors without any kind of priming. These cells also appear to distribute in secondary and tertiary lymphoid sites (i.e., spleen, bone marrow, liver, lung, and lymph nodes) both with and without stimulation. In addition to their ability to move throughout the body in an unprimed state, activated NK cells may have increased specificity in homing to sites of inflammation. NK cells not only react to, but also produce IFN-gamma, TNF-alpha, GM-CSF, CCL3, CCL4, and CCL5, enabling them to recruit various immune cells to sites of immune response.
Curr Mol Med 2004 Jun
PMID:Trafficking of natural killer cells. 1535 73

HC11, a spontaneously immortalized murine mammary lineage maintains features of normal cells while HC11 H-ras transformed cells (HC11 ras) are tumorigenic. Ras transformation is associated with a lower Vitamin D receptor (VDR) mRNA content. Our goal was to investigate the mechanism underlying VDR mRNA differences between these cells. Although the VDR transcriptional rate measured by run-on assays did not differ between the cells, our data suggested a pos transcriptional mechanism involving higher VDR mRNA degradation in HC11 ras cells which was not due to mutations in its 3'-UTR region since sequences of mRNA obtained from HC11 and HC11 ras cells were identical. Treatment of HC11 ras cells with a farnesyltransferase inhibitor, which prevents ras activation, causing an enhancement of VDR mRNA levels, indicating an association between the ras signaling pathway and VDR mRNA instability. The present work suggests that the decreased mRNA levels in HC11 ras cells might in part be due to an early loss of stability.
J Steroid Biochem Mol Biol 2004 Sep
PMID:Ras activation is associated with vitamin D receptor mRNA instability in HC11 mammary cells. 1554 34

Osteoporosis is a disease characterized by exaggerated loss of bone mass, with as much as 50 to 85% of the variation in bone mineral density (BMD) commonly accepted as being genetically determined. Although intensive studies have attempted to elucidate the genetic effects of polymorphisms on BMD and/or osteoporosis in several genes, the genes involved are still largely unknown. The possible associations of genetic variants in five-candidate genes (IL10, CCR3, MCP1, MCP2 and GC) with spinal BMD were investigated in Korean postmenopausal women (n = 370). Fourteen SNPs in five candidate genes were genotyped, and the haplotypes of each gene constructed. The associations of adjusted spinal BMD by age, year since menopause (YSM) and body mass index (BMI), with genetic polymorphisms, were analyzed using multiple regression models. Genetic association analysis of Korean postmenopausal women revealed that IL10 -592A > C and/or IL10 ht2 were associated with decreased bone mass, whereas no significant associations were observed with all polymorphisms in other genes. The levels of spinal BMD in individuals bearing the IL10 -592CC genotype were lower (0.78 +/- 0.16) than those in others (0.85 +/- 0.17) (P = 0.02), and the BMD of IL10 ht2 bearing individuals were also lower (0.82 +/- 0.15) than those in others (0.85 +/- 0.17) (P = 0.04). Our results suggest that variants of IL10 might play a role in the decreased BMD, although additional study might need to be followed-up in a more powerful cohort.
J Biochem Mol Biol 2004 Nov 30
PMID:Association of interleukin 10 haplotype with low bone mineral density in Korean postmenopausal women. 1560 28

Complement component C3a causes a robust degranulation in human mast cells. Whether C3a also stimulates chemokine production in human mast cells and what signaling pathway it activates is not known. In the present study, we demonstrate that CD34+ cell-derived primary mast cells and a human mast cell line LAD 2 express surface C3a receptors at similar levels. Furthermore, C3a caused approximately 50% internalization of cell surface C3a receptors in both cell types. We therefore used LAD 2 cells as a model to study C3a-induced biological responses and signaling in human mast cells. We found that C3a stimulated substantial degranulation and induced chemokine monocyte chemoattractant protein 1 (MCP-1/CCL2) and regulated upon activation, normal T-cell expressed and secreted (RANTES/CCL5) production in LAD 2 mast cells. C3a caused a rapid and sustained extracellular-signal-regulated kinase (ERK) phosphorylation and Akt phosphorylation in LAD 2 mast cells. Furthermore, U0126 and LY294002, which respectively inhibit MEK-induced ERK phosphorylation and PI3 kinase-mediated Akt phosphorylation had distinct effects on C3a-induced responses. Thus, U0126, which blocked C3a-induced RANTES/CCL5 production by 50.6+/-2.3%, inhibited MCP-1/CCL2 generation by 85.2+/-0.6%. In contrast, LY294002 had no effect on C3a-induced RANTES/CCL5 production but blocked MCP-1/CCL2 generation by 83.7+/-1.5%. These data demonstrate that C3a activates divergent signaling pathways to induce chemokine production in human mast cells.
Mol Immunol 2005 Mar
PMID:Distinct regulation of C3a-induced MCP-1/CCL2 and RANTES/CCL5 production in human mast cells by extracellular signal regulated kinase and PI3 kinase. 1560 17

Transcriptional silencing of the DNA repair gene, O6-methylguanine-DNA methyltransferase (MGMT) in a proportion of transformed cell lines is associated with methylated CpG hotspots in the MGMT 5' flank. The goal of the study was to evaluate the mechanism by which CpG methylation of theMGMT promoter region influenced silencing of the gene. Analysis of histone acetylation status in two regions of the promoter using chromatin immunoprecipitation assay showed that a higher level of histone acetylation was associated with expression in three MGMT-expressing cell lines (HeLa CCL2, HT29, and Raji) compared with three MGMT-silenced cell lines (HeLa S3, BE, and TK6). To determine how the modulation of CpG methylation and histone acetylation influenced MGMT expression, we exposed the cells to 5-aza-2'deoxycytidine (5-Aza-dC), inhibitor of DNA methylation, which strongly up-regulated MGMT expression in three MGMT-silenced cell lines whereas trichostatin A, inhibitor of histone deacetylase, weakly induced MGMT. However, combined treatment with 5-Aza-dC and trichostatin A significantly up-regulated MGMT RNA expression to a greater extent than in cells treated with either agent alone suggesting that histone deacetylation plays a role in MGMT silencing but that CpG methylation has a dominant effect. Consistent with enhanced MGMT expression, 5-Aza-dC increased the association of acetylated histone H3 and H4 bound to the MGMT promoter. Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT.
Mol Cancer Ther 2005 Jan
PMID:Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins. 1565 54

Insulin-like growth factor binding proteins (IGFBPs) -3 and -5 are known to interact with various components of the extracellular matrix (ECM; e.g. heparin and heparan sulphate) and this interaction is believed to affect the affinity of both IGFBP species for their cognate ligands--IGF-I and -II. There is little detail on the nature of the molecular complex formed between ECM components, IGFBPs and IGFs although the glycosaminoglycan (GAG) heparin has been reported to reduce the affinity of IGFBP-5 for IGF-I. In order to investigate this phenomenon further, we have undertaken an extensive surface plasmon resonance based biosensor study to report the affinity of IGFBP-3 and -5 for binding heparin (22 and 7 nM respectively). We have also shown that pre-complexation of IGFBP with IGF-I and -II inhibits the subsequent association of IGFBP with heparin and conversely that heparin complexation of IGFBP-3 and -5 inhibits IGFBP binding to biosensor surfaces containing immobilised IGF-I. In addition we have used both IGF-I and heparin coated biosensor surfaces in an attempt to build ternary IGF-IGFBP-heparin complexes in order to gain some insight into the nature of inhibition by heparin of IGFI-IGFBP complex formation. Our data lead us to conclude that the inhibition by heparin is partly competitive in nature, and that ternary complexes of IGF-IGFBP-heparin are either unable to form, or only form unstable transient complexes. The potential biological significance of our data is highlighted by the demonstration that IGF-I and IGF-II can displace endogenous IGFBP-5 from monolayer cultures of the mouse mammary epithelial cell line HC11.
J Mol Endocrinol 2005 Feb
PMID:Molecular recognition characteristics in the insulin-like growth factor (IGF)-insulin-like growth factor binding protein -3/5 (IGFBP-3/5) heparin axis. 1569 86

The secretory activation stage of mammary gland development occurs after parturition and converts inactive lobuloalveoli to active milk secretion. This process is triggered by progestin withdrawal and depends upon augmented prolactin (Prl) signaling. Little is known about the Prl-induced transcriptional changes that occur in the mammary gland to drive this process. To examine changes in the mammary transcriptome responsible for secretory activation, we have used transcript profiling of three mouse models that exhibit failure of secretory activation: knockout of galanin (a regulator of pituitary Prl production and a mammary cell autonomous modulator of Prl action); treatment with S179D Prl (a phosphoprolactin mimic); and knockout of a single Prl receptor allele. A significant reduction in expression was observed in genes belonging to 46 gene ontologies including those representing milk proteins, metabolism, lipid, cholesterol and fatty acid biosynthetic enzymes, immune response, and key transcription factors. A set of 35 genes, commonly regulated in all three models, was identified and their role in lactogenesis was validated by examining their expression in response to Prl stimulation or signal transducer and activator of transcription 5 knockdown in the HC11 mouse mammary cell culture model. The transcript profiles provided by these experiments identify 35 key genes (many for the first time) involved in the secretory activation phase of mammary gland development, show that S179D acts as an antagonist of Prl action, and provide insight into the partial penetrance of failed lactation in Prl receptor heterozygous females.
Mol Endocrinol 2005 Jul
PMID:Transcriptional changes underlying the secretory activation phase of mammary gland development. 1570 64

Angiogenesis is a dynamic process regulated by both local and systemic factors. Among these is vascular endothelial growth factor (VEGF), a potent effector of angiogenesis and vascular permeability. Previously we showed that VEGF is temporally and spatially regulated in the mouse mammary gland during development and lactation. Given the functions of prolactin (PRL) during these stages and the supporting role of the vasculature, we investigated the regulation of VEGF by PRL. Treatment of HC11 mouse mammary epithelial and Nb2 rat lymphoma cells with PRL induced VEGF expression. Deletion and mutation analysis identified a GC-rich region in the proximal region of the VEGF promoter that constitutively bound Sp1 and PRL-induced Egr-1. These sites conferred PRL-responsiveness leading to increased VEGF transcription. The induction of VEGF by PRL was PRL receptor-, Jak2- and MAP kinase kinase-dependent. Our results indicate that PRL induces VEGF expression through Egr-1, and implicates VEGF as an intermediary of PRL-regulated angiogenesis.
Mol Cell Endocrinol 2005 Mar 31
PMID:Prolactin-induced expression of vascular endothelial growth factor via Egr-1. 1573 64


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