UNIPROT:P10145 - FACTA Search

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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear translocation of beta-catenin and its association with Tcf/Lef factors are key steps in transduction of the Wnt signal, which is aberrantly activated in a variety of human cancers. In a search for new beta-catenin-Tcf target genes, we analyzed beta-catenin-induced alterations of gene expression in primary human hepatocytes, after transduction of either dominant stable beta-catenin or its truncated, transactivation-deficient counterpart by means of a lentiviral vector. cDNA microarray analysis revealed a limited set of up-regulated genes, including known Wnt targets such as matrilysin and keratin-1. In this screen, we identified the CXC chemokine interleukin 8 (IL-8) as a direct target of beta-catenin-Tcf4. IL-8 is constitutively expressed in various cancers, and it has been implicated in tumor progression through its mitogenic, motogenic, and angiogenic activities. The IL-8 promoter contains a unique consensus Tcf/Lef site that is critical for IL-8 activation by beta-catenin. We show here that the p300 coactivator was required for efficient transactivation of beta-catenin on this promoter. Ectopic expression of beta-catenin in hepatoma cells promoted IL-8 secretion, which stimulated endothelial cell migration. These data define IL-8 as a Wnt target and suggest that IL-8 induction by beta-catenin might be implicated in developmental and tumorigenic processes.
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PMID:Transcriptional activation of interleukin-8 by beta-catenin-Tcf4. 1220 Apr 48

We have demonstrated recently that PTHrP is upregulated in pancreatic adenocarcinoma and that the ECM exerts regulatory control, at least in part, over PTHrP expression. In our present study, we examined the potential signaling interactions between these 2 pathways. Our results demonstrate that, under serum-free conditions, adhesion of FG pancreatic adenocarcinoma cells on Fn is mediated by the alpha5beta1 integrin, whereas adhesion to Type I collagen is mediated by the alpha2beta1 integrin. alpha5beta1 integrin-mediated adhesion to Fn results in a phenotype that includes a reduction in cell proliferation, increased E-cadherin localization in cell-cell contacts, increased beta-catenin localization throughout the cell, inhibition of haptokinetic cell migration, and increased expression of PTHrP, IL-6 and IL-8 relative to alpha2beta1 integrin-mediated adhesion on Type I collagen. A phosphoprotein immunoblotting screen of FG pancreatic cancer cells grown on either Fn or Type I collagen indicates that GSK3 and PKB/Akt are differentially phosphorylated on these 2 substrates. These results implicate GSK3 and PKB/Akt in the integrin-mediated regulation of PTHrP, IL-6 and IL-8 in pancreatic cancer.
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PMID:GSK3 and PKB/Akt are associated with integrin-mediated regulation of PTHrP, IL-6 and IL-8 expression in FG pancreatic cancer cells. 1560 21

Salmonella-epithelial cell interactions are known to activate the proinflammatory NF-kappaB signaling pathway and have recently been found to also influence the beta-catenin signaling pathway, an important regulator of epithelial cell proliferation and differentiation. Here, using polarized epithelial cell models, we demonstrate that these same bacteria-mediated effects also direct the molecular crosstalk between the NF-kappaB and beta-catenin signaling pathways. Convergence of these two pathways is a result of the direct interaction between the NF-kappaB p50 subunit and beta-catenin. We show that PhoP(c), the avirulent derivative of a wild-type Salmonella strain, attenuates NF-kappaB activity by stabilizing the association of beta-catenin with NF-kappaB. In cell lines expressing constitutively active beta-catenin, IkappaBalpha protein was indirectly stabilized and NF-kappaB activity was repressed after wild-type Salmonella colonization. Accordingly, constitutively active beta-catenin was found to inhibit the secretion of IL-8. Thus our findings strongly suggest that the crosstalk between the beta-catenin and NF-kappaB signaling pathways is an important regulator of intestinal inflammation.
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PMID:Crosstalk between NF-kappaB and beta-catenin pathways in bacterial-colonized intestinal epithelial cells. 1579 Jul 58

Wnts are secreted signaling proteins able to control diverse biological processes such as cell differentiation and proliferation. Many Wnts act through a canonical, beta-catenin signaling pathway. Here, we report that Wnt receptors and transcriptional effectors are expressed in primary human endothelial cells and that Wnt/beta-catenin signaling promotes angiogenesis. Human umbilical vein and microvascular endothelial cells express Wnt receptors, Frizzled-4, -5, -6, and beta-catenin-associated transcription factors, Tcf-1, -3, -4 and Lef-1. In endothelial cells, ectopic expression of Wnt-1 stabilized cytosolic beta-catenin, demonstrating activation of the Wnt/beta-catenin canonical signaling pathway. Expression of Wnt-1 or a stabilized and active form of beta-catenin, beta-cateninS37A, promoted endothelial cell proliferation. Proliferation induced by Wnt/beta-catenin signaling was optimal in the presence of bFGF. beta-cateninS37A expression in endothelial cells promoted survival after growth factor deprivation. Using matrigel assays, Wnt-1 or beta-cateninS37A expression promoted the formation of capillary-like networks. To help define the effectors of Wnt angiogenic function, microarray analysis was used to compare endothelial cells expressing Wnt-1 to control cells. Interleukin-8, a known angiogenic factor, was identified as a transcriptional target of Wnt/beta-catenin signaling in endothelial cells. Expression of either Wnt-1 or beta-cateninS37A induced Interleukin-8 transcripts and secreted protein. We thus conclude that Wnt/beta-catenin signaling promotes angiogenesis possibly via the induction of known angiogenic regulators such as Interleukin-8.
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PMID:Wnt/beta-catenin signaling induces proliferation, survival and interleukin-8 in human endothelial cells. 1613 17

Pancreatic cancer is one of the most lethal tumours of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and/or chemotherapy would be a great clinical asset. Considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological variables of pancreatic tumours and survival. This systematic review examined evidence from published manuscripts looking at molecular markers in pancreatic cancer and their correlation with tumour stage and grade, response to chemotherapy and long-term survival. A literature search was undertaken using PubMed and MEDLINE search engines, using the keywords p53, p21, p16, p27, SMAD4, K-ras, cyclin D1, Bax, Bcl-2, EGFR, EGF, c-erbB2, HB-EGF, TGFbeta, FGF, MMP, uPA, cathepsin, heparanase, E-cadherin, laminins, integrins, TMSF, CD44, cytokines, angiogenesis, VEGF, IL-8, beta-catenin, DNA microarray, and gene profiling. A bewildering number of biomarkers are currently under evaluation. For the most part, the evidence regarding their application as prognostic indicators is conflicting. The advent of gene microarray and mass spectrometric protein profiling offers the potential to examine many different biomarkers simultaneously. This 'protein/gene signature' could revolutionise work in this field and allow researchers to develop accurate and reproducible predictions of survival based on protein or gene profiles.
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PMID:Molecular prognostic markers in pancreatic cancer: a systematic review. 1614 90

Angiopoietin-1 (ANGPT1), Angiopoietin-4 (ANGPT4), VEGF, FGF2, FGF4, HGF, Ephrin, IL8 and CXCL12 (SFD1) are pro-angiogenic factors (angiogenic activators), while Angiopoietin-2 (ANGPT2), Angiostatin, Endostatin, Tumstatin, Canstatin, THBS1, THBS2, TNFSF15 (VEGI) and Vasohibin (VASH1) are anti-angiogenic factors (angiogenic inhibitors). ANGPT1 and ANGPT2 are ligands for TIE family receptor tyrosine kinases, TIE1 and TIE2 (TEK). Angiopoietin family consists of ANGPT1, ANGPT2, ANGPT4, ANGPTL1 (ANGPT3), ANGPTL2, ANGPTL3 (ANGPT5), ANGPTL4, ANGPTL5, ANGPTL6 and ANGPTL7. TCF/LEF binding sites within the promoter region of human Angiopoietin family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the human ANGPTL7 promoter, comparative genomics analyses on ANGPTL7 orthologs were further performed. ANGPTL7 gene at human chromosome 1p36.22 was located within intron 28 of FRAP1 gene encoding mTOR protein. Chimpanzee ANGPTL7 gene, consisting of five exons, was located within NW_101546.1 genome sequence. Chimpanzee ANGPTL7 showed 99.4% and 86.1% total-amino-acid identity with human ANGPTL7 and mouse Angptl7, respectively. Human ANGPTL7 mRNA was expressed in neural tissues, keratoconus cornea, trabecular meshwork, melanotic melanoma and uterus endometrial cancer, while mouse Angptl7 mRNA was expressed in four-cell embryo, synovial fibroblasts, thymus, uterus and testis. Four TCF/LEF-binding sites within human ANGPTL7 promoter were conserved in chimpanzee ANGPTL7 promoter; however, only an unrelated TCF/LEF-binding site occurred in mouse and rat Angptl7 promoters. Human ANGPTL7, characterized as potent target gene of WNT/ beta-catenin signaling pathway, is a pharmacogenomics target in the fields of oncology and regenerative medicine.
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PMID:Comparative integromics on Angiopoietin family members. 1668 28

Wild-type (WT) Salmonella typhimurium causes acute intestinal inflammation by activating the nuclear factor kappa B (NF-kappaB) pathway. Interestingly, WT Salmonella infection also causes degradation of beta-catenin, a regulator of cellular proliferation. Regulation of beta-catenin and the inhibitor of NF-kappaB, IkappaBalpha, is strikingly similar, involving phosphorylation at identical sites, ubiquitination by the same E3 ligase, and subsequent proteasomal degradation. However, how beta-catenin directly regulates the NF-kappaB pathway during bacteria-induced inflammation in vivo is unknown. Using streptomycin-pretreated mice challenged with Salmonella, we demonstrated that WT Salmonella stimulated beta-catenin degradation and decreased the physical association between NF-kappaB and beta-catenin. Accordingly, WT Salmonella infection decreased the expression of c-myc, a beta-catenin-regulated target gene, and increased the levels of IL-6 and TNF-alpha, the NF-kappaB-regulated target genes. Bacterial infection directly stimulated phosphorylation of beta-catenin, both in vivo and in vitro. Closer examination revealed that glycogen synthase kinase 3beta (GSK-3beta) kinase activity was increased in response to WT Salmonella, whereas non-virulent Salmonella had no effect. siRNA of GSK-3beta was able to stabilize IkappaBalpha in response to WT Salmonella. Pretreatment for 24 h with LiCl, an inhibitor of GSK-3beta, reduced WT Salmonella induced IL-8 secretion. Additionally, cells expressing constitutively active beta-catenin showed IkappaBalpha stabilization and inhibition of NF-kappaB activity not only after WT Salmonella infection but also after commensal bacteria (Escherichia coli F18) and TNF-alpha treatment. This study suggests a new role for beta-catenin as a negative regulator of inflammation.
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PMID:beta-Catenin activity negatively regulates bacteria-induced inflammation. 1738 65

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling, while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.
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PMID:Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. 1756 83

In the anterior pituitary gland, inflammatory mediators regulate cell function through an immuno-endocrine pathway. Recent studies have shown that undifferentiated stem cells act as immunomodulators. These studies prompted us to establish a progenitor cell line from the bovine anterior pituitary gland and to detail its function. First, we localised interleukin (IL)-18 by immunohistochemistry to the marginal cell layer of Rathke's pouch that is assumed to embody a stem/progenitor cell compartment of the postnatal pituitary gland. A cloned anterior pituitary-derived cell line from the bovine anterior pituitary gland was established from single cell clone by the limiting dilution method and was designated as bovine anterior pituitary-derived cell line (BAPC)-1. BAPC-1 cells constantly expressed mRNAs for IL-18 and IL-18 receptor, and grew steadily and rapidly in the medium containing epidermal growth factor and basic fibroblast growth factor. The cell line also expressed the mRNAs for the stem/progenitor cell- related factors such as Nanog, Oct-4, Ptch1, Nestin, Notch1, Hes1, Lrp and Fzd4, and the mRNAs for embryonic pituitary-related factors, such as Lhx3, PitX1 and Pit-1. The nuclei of BAPC-1 were immunostained positively for Pit-1, Hes1 and beta-catenin antibodies. Furthermore, BAPC-1 cells expressed mRNAs for cytokine such as IL-1alpha, IL-6, IL-7, IL-12 and IL-15. Stimulation of BAPC-1 cells with IL-18 increased expression of mRNAs for IL-1alpha, IL-6, IL-1beta and IL-8. At day 6 in culture, BAPC-1 cells also express growth hormone mRNA. These results strongly suggest that BAPC-1 is a stem/progenitor cell line and modulates the immuno-endocrine function of the anterior pituitary cells through its cytokine production.
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PMID:Bovine anterior pituitary progenitor cell line expresses interleukin (IL)-18 and IL-18 receptor. 1876 16

Elevated deoxycholic acid (DCA), mutations in the adenomatous polyposis coli (APC) gene and chronic inflammation are associated with increased risk of colorectal cancer. APC status was manipulated to determine whether DCA mediates inflammatory molecules in normal or initiated colonic mucosa. DCA increased steady state mRNA and protein levels of CXCL8 in cells which do not express wild-type APC. Steady-state CXCL8 mRNA and protein were suppressed when cells with conditional expression of wild-type APC were exposed to DCA. Immunostaining did not detect CXCL8 in normal human colonic mucosa. CXCL8 was expressed in adenomatous polyps and adenocarcinomas. CXCL8 expression correlated with nuclear beta-catenin localization in epithelial cells of adenomas, but was associated with endothelial cells and neutrophils in the adenocarcinomas. DCA-mediated CXCL8 promoter-reporter activity was elevated in a mutant APC background. Wild-type APC suppressed this effect. Mutation of activator protein-1 (AP-1) or nuclear factor kappa B (NF-kappaB) sites suppressed the activation of the CXCL8 promoter-reporter by DCA. Chromatin immunoprecipitation revealed that AP-1 and NF-kappaB binding to the 5'-promoter of CXCL8 was induced by DCA. The beta-catenin transcription factor was bound to the 5'-promoter of CXCL8 in the absence or presence of DCA. Phenotypic assays determined that DCA-mediated invasion was blocked by antibody-directed against CXCL8 or wild-type APC. CXCL8 exposure led to matrix metalloproteinase-2 production and increased invasion on laminin-coated filters. These data suggest that DCA-mediated CXCL8 occurs in initiated colonic epithelium and neutralizing CXCL8 could reduce the invasive potential of tumors.
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PMID:Regulation of deoxycholate induction of CXCL8 by the adenomatous polyposis coli gene in colorectal cancer. 1917 96

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