Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A serious insulin resistance characterizes pancreatic cancer-associated diabetes mellitus. Elsewhere, we demonstrated that MIA PaCa2 cultured cells secrete a soluble factor responsible for reduced glucose tolerance induced in SCID mice. The intracellular mechanism of insulin resistance was investigated in isolated and perfused rat hepatocytes incubated with MIA PaCa2 conditioned medium. Lactate production was reduced compared to hepatocytes incubated with control medium while 1,2-DAG was increased and PKC was activated in the hepatocytes incubated with MIA PaCa2 conditioned medium. This behavior was not reproduced treating the hepatocytes with the growth factors EGF, interleukin Ibeta, interleukin-6, and TGF-beta1. In an attempt to make a biochemical identification of the hypothesized tumor associated-diabetogenic factors we observed a low molecular weight protein in the conditioned medium, absent in the nonconditioned one, that may be responsible for the described behaviors.
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PMID:Glucose metabolic alterations in isolated and perfused rat hepatocytes induced by pancreatic cancer conditioned medium: a low molecular weight factor possibly involved. 1019 61

Although it is generally accepted that destruction and remodeling of temporal bone associated with middle ear cholesteatoma is mainly caused by the action of osteoclasts, it has been shown that neutral collagenases also play a role in predigesting the osteoid layer and exposing the mineralized bone to osteoclastic activity. Here we show that gelatinase B (matrix metalloproteinase-9) is over-expressed in cholesteatoma compared to external ear canal skin (EACS). Expression of MMP-9 in cholesteatoma mainly occurs in suprabasal layers, and more rarely in basal layers of cholesteatoma epithelium, as well as in inflammatory cells of the perimatrix. We further analyzed the influence of cholesteatoma debris, cholesteatoma granulation tissue, and cholesteatoma components such as keratin, cholesterol and bacterial endotoxin on the expression of MMPs in EACS keratinocytes. We show that cholesteatoma debris and granulation tissue extract both induced the secretion of MMP-9 by EACS keratinocytes, while keratin. bacterial lipopolysaccharide (LPS) or cholesterol did not show any effect. We further performed co-incubation and immunoprecipitation experiments using neutralizing interleukin-1alpha, EGF, TGF-beta, TGF-alpha, interleukin-6 and TNF-alpha antibodies. Inhibition of MMP-9 up-regulation by debris or granulation tissue extract could be revealed with diverse cytokine antibodies. The results are discussed with regard to previously published studies.
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PMID:Induction of matrix metalloproteinases in keratinocytes by cholesteatoma debris and granulation tissue extracts. 1107 91

The plasma level of interleukin-6 (IL-6) is elevated in patients with acute coronary syndromes and has prognostic value. Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. We examined the mechanism of thrombin-induced IL-6 expression in VSMCs. Thrombin induced IL-6 mRNA and protein expression in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (MAPK), or epidermal growth factor receptor (EGF-R) suppressed the thrombin-induced IL-6 expression. Deletion and mutation analysis of the promoter region of the IL-6 gene by using luciferase as a reporter showed that the DNA segment between -228 and -150 bp containing the cAMP response element (CRE) site played a critical role. Thrombin also induced phosphorylation of CRE binding protein (CREB) in an ERK- and a p38 MAPK-dependent manner. Overexpression of the dominant-negative form of CREB inhibited thrombin-induced IL-6 mRNA expression. These results suggest that the CRE site and CREB play an important role in thrombin-induced IL-6 gene expression in VSMCs. Transactivation of EGF-R and activation of ERK and p38 MAPK are involved in this process. CREB may be a novel transcription factor that regulates thrombin-induced gene expression.
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PMID:Thrombin induces interleukin-6 expression through the cAMP response element in vascular smooth muscle cells. 1170 62

Oncostatin M (OSM), an interleukin-6 type cytokine, acts via the gp130 signaling receptor to inhibit proliferation and induce differentiation of breast cancer cells. EGF, a mitogen for breast cells, signals via EGFR/ErbB tyrosine kinase receptors which are implicated in breast cancer pathogenesis. Here we show paradoxically that EGF enhanced the OSM-induced inhibition of proliferation and induction of cellular differentiation in both estrogen receptor positive and negative breast cancer cells. This functional synergism was also seen with heregulin but not SCF, PDGF or IGF-1, indicating that it was specific to EGF-related growth factors. Immunoprecipitation experiments revealed that gp130 was constitutively associated with ErbB-2 and ErbB-3. There was a similar association between the OSMRbeta and ErbB-2. Furthermore, EGF unexpectedly induced tyrosine phosphorylation of gp130. We show that OSM induced phosphorylation of STAT3. Both OSM and EGF activated the p42/44 MAP kinases, but while the MEK inhibitor, PD98059, ablated the OSM-induced inhibition, it only partially ablated the inhibitory effects of OSM plus EGF. Thus, we have demonstrated that the receptors and signalling pathways of two apparently unrelated growth factors were intimately linked, resulting in an unexpected biological effect. This provides a new mechanism for generating signalling diversity and has potential clinical implications in breast cancer.
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PMID:An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. 1182 58

EGF (epidermal growth factor) binding to its receptor (EGFR) induces dimerization and autophosphorylation of the receptor at multiple tyrosine residues, which serve as docking sites for recruitment of proteins with SH2 (Src homology 2) domains that activate multiple downstream signalling pathways. The adaptor protein Grb2 (growth factor receptor-binding protein 2) binds to EGFR, which leads to activation of Ras-MAPK (mitogen-activated protein kinase) cascade. The latent transcription factors, STAT (signal transduction and activator of transcription), can also be activated by EGF in certain cell types. Since Ras-MAPK and STAT pathways are simultaneously stimulated by EGF, and Tyr-1086 and Tyr-1068 of EGFR are reported to be the binding sites for both Grb2 and Stat3, we investigated the possible regulatory role of Grb2 in STAT activation. In the present study, we report that transient expression of Grb2 specifically down-regulates EGF-stimulated tyrosine phosphorylation of Stat3, which leads to a repression of Stat3 transcriptional activity. In contrast, depletion of Grb2 by RNA interference substantially increases Stat3 tyrosine phosphorylation induced by EGF. The inhibition is neither mediated by a direct interaction between Grb2 and Stat3 nor via activation of tyrosine phosphatases. However, the repression was abolished by a mutation in the SH2 domain, but not the SH3 domains of Grb2, suggesting that inhibition involves binding of the receptor. Indeed, Grb2 inhibits the interaction between Stat3 and EGFR by competitive binding to the EGFR. On the other hand, Grb2 does not interact with the same sites as Stat3 on the interleukin-6 receptor and, therefore, has no effect on interleukin-6-induced tyrosine phosphorylation of Stat3. Taken together, our results demonstrate that, in EGF signalling, Grb2 regulates Stat3 activation negatively at the receptor level.
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PMID:Grb2 regulates Stat3 activation negatively in epidermal growth factor signalling. 1449 32

A STAT3 (signal transducer and activator of transcription 3)- and a MEK/Erk-mediated signal can be activated by cytokines, including IL-6 (interleukin-6), PDGF, and EGF. Recently, STAT3 and an ERK-signal were shown to co-operatively activate the c-fos gene. Activation of a truncated form of the IL-6 receptor subunit, gp130, that had only one YXXQ motif, induced both c-Fos and JunB in NIH3T3 cells through STAT3 without an apparent increase in the AP-1 (activator protein-1) activity. In contrast, concomitant stimulation of the STAT3 signal and a MEK/Erk-signal markedly increased AP-1 activity with enhanced c-Fos expression. Surprisingly, the c-Fos induced by the YXXQ-signal alone was localized to the cytoplasm, from which it translocated into the nucleus following TPA (12-O-tetradecanoyl-phorbol 13-acetate) treatment in a MEK/Erk-dependent manner. c-Fos that was expressed from a constitutive promoter localized to the nucleus and did not move into the cytoplasm in response to the YXXQ-signal. Rather, the YXXQ-signal was required during c-Fos production for it to be retained in the cytoplasm. Thus, the YXXQ-signal induces c-Fos expression through STAT3 and anchors the new c-Fos in the cytoplasm. In addition, the YXXQ-signal and an Erk signal co-operatively cause c-Fos activation in the nucleus.
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PMID:Cytoplasmic c-Fos induced by the YXXQ-derived STAT3 signal requires the co-operative MEK/ERK signal for its nuclear translocation. 1500 10

The interleukin-6 (IL6) family of cytokines signals through the common receptor subunit gp130, and subsequently activates Stat3, MAPK, and PI3K. Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution, which is partially induced by IL6 and LIF. However, it is not clear whether Stat3 activation is mediated solely through the gp130 pathway or also through other receptors. This question was explored in mice carrying two distinct mutations in the gp130 gene; one that resulted in the complete ablation of gp130 and one that led to the loss of Stat3 binding sites (gp130Delta/Delta). Deletion of gp130 specifically from mammary epithelium resulted in a complete loss of Stat3 activity and resistance to tissue remodeling comparable to that seen in the absence of Stat3. A less profound delay of mammary tissue remodeling was observed in gp130Delta/Delta mice. Stat3 tyrosine and serine phosphorylation was still detected in these mice suggesting that Stat3 activation could be the result of gp130 interfacing with other receptors. Experiments in primary mammary epithelial cells and transfected COS-7 cells revealed a p44/42 MAPK and EGFR-dependent Stat3 activation. Moreover, the gp130-dependent EGFR activation was independent of EGF ligands, suggesting a cytoplasmic interaction and cross-talk between these two receptors. These experiments establish that two distinct Stat3 signaling pathways emanating from gp130 are utilized in mammary tissue.
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PMID:Mammary gland remodeling depends on gp130 signaling through Stat3 and MAPK. 1529 6

Neural stem cells (NSC) are capable of differentiating toward neuronal, astrocytic, oligodendrocytic and glial lineages, depending on their spatial location within the central nervous system (CNS). Although, a lot of knowledge has been gained in the understanding of differentiation-specific signaling in hematopoietic (HSC) and mesenchymal (MSC) counterparts, the molecular mechanisms underlying lineage commitment in NSCs are just beginning to be understood. Furthermore, it is not well comprehended as to how the specification of one cell lineage can result in the suppression of parallel pathways in the NSCs. Thus, a thorough understanding of various signal transduction cascades activated via cytokines and growth factors, and the confounding effects of different CNS microenvironments are critically required to determine the full potential of NSCs. Our knowledge on the clonogenic ability, differentiation potential, and the inherent plasticity in both HSCs and MSCs may facilitate the understanding of lineage commitment in the NSCs as well. The information available from the marrow-derived stem cells may be extrapolated toward the similar signaling pathways in the neural precursors. From a number of previous studies, it is apparent that four distinctly different subsets of ligand-receptor superfamilies are involved in determining the fate of NSCs. These include 1) the transforming growth factor type-beta-1 (TGF-beta1) and bone morphogenetic protein (BMP) superfamily; 2) the platelet-derived and epidermal (PDGF/EGF) growth factors; 3) the interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor (IL-6/LIF/CNTF) superfamily; and 4) the EGF-like Notch/Delta group of extracellular ligands. Ligand binding to the cell surface receptor activates the receptor's cytosolic catalytic domain and/or the receptor-associated protein-kinases, which in turn activate intracellular second messengers and different sets of transcription factors. Transcription factor oligomerization, nuclear localization, followed by their recognition of DNA elements, leads to the expression of lineage-specific genes. Association between different groups of transcription factors can also regulate their ability to transcriptionally activate different genes. The limited availability of coactivators and cosuppressors, which can sequester the transcription factor complexes toward or away from a specific gene locus, further adds to the complexity in the cross talk between different signaling cascades. Both concerted actions of temporally regulated signals and convergent effects of different signaling cascades can thus ultimately precipitate the phenotypic changes. It is beginning to be realized that in addition to the cytokines and growth factors, cell-to-cell and cell-to-extracellular matrix (ECM) interactions, are also important within the molecular scenario linked to both proliferation and differentiation of the stem cells. The cell surface molecules, which include cell adhesion molecules (CAMs), integrins, selectins, and the immunoglobulins, are well known to regulate HSC and MSC commitment within different tissue microenvironments and may have direct implications in understanding the NSC cell fate determination within different regions of the brain.
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PMID:Signal transduction pathways involved in the lineage-differentiation of NSCs: can the knowledge gained from blood be used in the brain? 1564 90

The exact role of the soluble form of epidermal growth factor receptor (sEGF-R) in melanoma disease remains to be determined. We focused this study on the detection of circulating levels of sEGF-R in metastatic malignant melanoma patients and on the possible relationship between sEGF-R and clinicobiological parameters including circulating interleukin-6 (IL-6) and survival. sEGF-R and IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay in serum from 75 metastatic malignant melanoma patients and 30 healthy controls. In our patients, median sEGF-R level was significantly elevated (P < 0.0001) compared with that of healthy controls (173.4 vs. 91.9 fm/ml). Age or sex was not associated with sEGF-R levels. Regarding tumor burden, in contrary to the detected IL-6 levels, we found that median sEGF-R levels were significantly (P = 0.045) lower in patients with high tumor burden (163 fm/ml) than in those with low tumor burden (193.8 fm/ml). An inverse correlation between IL-6 levels and sEGF-R was observed (r =-0.33; P = 0.040). No relationship between sEGF-R and time to progression or overall survival was observed while circulating IL-6 was found as a predictive factor of survival. Our results showed that sEGF-R level was elevated in metastatic malignant melanoma patients but not related to time to progression or survival and demonstrated an inverse correlation between sEGF-R and IL-6 levels. These findings imply a better understanding of EGF-R and IL-6 cross-talk function in melanoma.
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PMID:An unexpected inverse correlation between soluble epidermal growth factor receptor and interleukin-6 in metastatic malignant melanoma patients. 1684 29

Wound fluids, human serum from platelet-poor and platelet-rich plasma (SPPP and SPRP), contain various soluble factors involved in cell growth and proliferation. Levels of cytokines, chemokines, and matrix metalloproteinases (MMPs) in drainage fluids (DFs) harvested from subcutaneous wounds, punctured fluids (PF) from seroma, and SPPP were measured. SPPP and SPRP from four healthy volunteers were also subjected to the analysis. Biochemical profiles of DF reflected the sequential stages of wound healing. Early-phase DF contained high concentrations of basic fibroblast growth factor and platelet-derived growth factor and EGF. The levels of keratinocyte growth factor, interleukin-6, and MMP-8 in DF peaked on days 2-3, while vascular endothelial growth factor, hepatocyte growth factor, interleukin-8, and MMP-1 increased over time during days 0-6. Punctured fluids contained high levels of TGF-beta1, keratinocyte growth factor, vascular endothelial growth factor, hepatocyte growth factor, and MMP-1. Experiments using human adipose-derived stem cells and dermal fibroblasts cultured in media containing various concentrations of DF and fetal bovine serum suggested that for some cell types, DF-contained growth factors that are not obtained from SPRP could be used to supplement or substitute for serum in culture media. SPRP and DF are economical ready-made mixtures of serum and autologous soluble factors, and may be differentially useful for regenerative therapies.
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PMID:Characterization of wound drainage fluids as a source of soluble factors associated with wound healing: comparison with platelet-rich plasma and potential use in cell culture. 1765 95


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