Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HER2/neu overexpression is a driving force in the carcinogenesis of several human cancers. In breast cancer the prognostic influence of HER2/neu was shown to be at least partly based on increased metastatic potential mediated by the chemokine-chemokine receptor pair SDF-1(CXCL12)/CXCR4. We wanted to evaluate the influence of HER2/neu on ovarian cancer prognosis and to investigate whether compromised survival would correlate with CXCR4 expression and/or SDF-1 abundance. Therefore, we analysed HER2/neu, CXCR4, and SDF-1 in 148 ovarian tumour samples by means of immunohistochemistry on tissue microarrays. Overexpression of HER2/neu was found in 27.6% of ovarian cancer tissues and in 15% of ovarian borderline tumours. In ovarian cancer patients, overexpression of HER2/neu correlated closely with overall survival (univariate hazard ratio (HR) 2.59, P=0.005; multiple corrected HR 1.92, P=0.074). In contrast, CXCR4 expression and SDF-1 abundance had no impact on overall survival, and both parameters were not correlated with HER2/neu expression. As expected, cytoplasmic CXCR4 expression and SDF-1 abundance correlated closely (P<0.0001). Our results confirm a univariate influence of HER2/neu expression on overall survival, which was completely independent of the expression of CXCR4 and the abundance of SDF-1, implying significant differences between the HER2/neu downstream pathways in ovarian cancer compared with breast cancer.
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PMID:In ovarian cancer the prognostic influence of HER2/neu is not dependent on the CXCR4/SDF-1 signalling pathway. 1724 39

Cyclic diguanylate (c-di-GMP) is a bacterial intracellular signaling molecule. We have shown that treatment with exogenous c-di-GMP inhibits Staphylococcus aureus infection in a mouse model. We now report that c-di-GMP is an immodulator and immunostimulatory molecule. Intramammary treatment of mice with c-di-GMP 12 and 6 h before S. aureus challenge gave a protective effect and a 10,000-fold reduction in CFUs in tissues (p < 0.001). Intramuscular vaccination of mice with c-di-GMP coinjected with S. aureus clumping factor A (ClfA) Ag produced serum with significantly higher anti-ClfA IgG Ab titers (p < 0.001) compared with ClfA alone. Intraperitoneal injection of mice with c-di-GMP activated monocyte and granulocyte recruitment. Human immature dendritic cells (DCs) cultured in the presence of c-di-GMP showed increased expression of costimulatory molecules CD80/CD86 and maturation marker CD83, increased MHC class II and cytokines and chemokines such as IL-12, IFN-gamma, IL-8, MCP-1, IFN-gamma-inducible protein 10, and RANTES, and altered expression of chemokine receptors including CCR1, CCR7, and CXCR4. c-di-GMP-matured DCs demonstrated enhanced T cell stimulatory activity. c-di-GMP activated p38 MAPK in human DCs and ERK phosphorylation in human macrophages. c-di-GMP is stable in human serum. We propose that cyclic dinucleotides like c-di-GMP can be used clinically in humans and animals as an immunomodulator, immune enhancer, immunotherapeutic, immunoprophylactic, or vaccine adjuvant.
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PMID:Bacterial c-di-GMP is an immunostimulatory molecule. 1727 22

Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine involved in the pathogenesis of inflammatory diseases of the lung. Interleukin-8 (IL-8), a C-X-C chemokine, is induced by TNF-alpha and initiates injury by acting as a chemoattractant for neutrophils and other immune cells. Although sphingolipids such as ceramide and sphingosine 1-phosphate (S1-P) have been shown to serve as signaling molecules in the TNF-alpha inflammatory response, their role in the TNF-alpha induction of IL-8 gene expression in lung epithelial cells is not known. We investigated the role of sphingolipids in the TNF-alpha induction of IL-8 gene expression in H441 lung epithelial cells. We found that TNF-alpha induced IL-8 mRNA levels by increasing gene transcription, and the stability of IL-8 mRNA was not affected. Exogenous S1-P but not ceramide or sphingosine increased IL-8 mRNA levels and IL-8 secretion. Dimethylsphingosine, an inhibitor of sphingosine kinase, partially inhibited TNF-alpha induction of IL-8 mRNA levels indicating the importance of intracellular increases in S1-P in the IL-8 induction. S1-P induction of IL-8 mRNA was due to an increase in gene transcription, and the stability of IL-8 mRNA was not affected. S1-P induction of IL-8 mRNA was associated with an increase in the binding activity of AP-1 but the activities of NF-kappaB and NF IL-6 were unchanged. S1-P induced the phosphorylation of ERK, p38 and JNK MAPKs. Pharmacological inhibitors of ERK and p38 but not JNK partly inhibited S1-P induction of IL-8 mRNA levels. These data show that increases in the intracellular S1-P partly mediate TNF-alpha induction of IL-8 gene expression in H441 lung epithelial cells via ERK and p38 MAPK signaling pathways and increased AP-1 DNA binding.
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PMID:The role of sphingosine 1-phosphate in the TNF-alpha induction of IL-8 gene expression in lung epithelial cells. 1730 37

Bacterial pneumonia remains a serious disease and is associated with neutrophil recruitment. Innate immunity is pivotal for the elimination of bacteria, and TLRs are essential in this process. Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF) is an adaptor for TLR3 and TLR4, and is associated with the MyD88-independent cascade. However, the importance of TRIF in immune responses against pulmonary bacterial pathogens is not well understood. We investigated the involvement of TRIF in a murine model of Escherichia coli pneumonia. TRIF(-/-) mice infected with E. coli display attenuated neutrophil migration; NF-kappaB activation; and TNF-alpha, IL-6, and LPS-induced C-X-C chemokine production in the lungs. In addition, E. coli-induced phosphorylation of JNK, ERK, and p38 MAPK was detected in bone marrow-derived macrophages (BMMs) of TRIF(+/+) mice, but attenuated in BMMs of TRIF(-/-) mice. Furthermore, E. coli-induced TNF-alpha and IL-6 production was attenuated in BMMs of TRIF(-/-) mice. E. coli LPS-induced late MAPK activation, and TNF-alpha and IL-6 production were abolished in BMMs of TRIF(-/-) mice. Moreover, TRIF is not required for LPS-induced neutrophil influx, and keratinocyte cell-derived chemokine, MIP-2, and LPS-induced C-X-C chemokine production in the lungs. Using TLR3(-/-) mice, we ruled out the role of TLR3-mediated TRIF-dependent neutrophil influx during E. coli pneumonia. A TLR4-blocking Ab inhibited E. coli-induced TNF-alpha and IL-6 in BMMs of both TRIF(-/-) and TRIF(+/+) mice, suggesting that TRIF-mediated signaling involves TLR4. We also found that TRIF is critical to control E. coli burden in the lungs and E. coli dissemination. Thus, rapid activation of TRIF-dependent TLR4-mediated signaling cascade serves to augment pulmonary host defense against a Gram-negative pathogen.
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PMID:Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling contributes to innate immune responses in the lung during Escherichia coli pneumonia. 1731 63

Insulin-like growth factor (IGF) signaling is a critical regulator of somatic growth during fetal and adult development, primarily through its stimulatory effects on cell proliferation and survival. IGF signaling is also required for development of the reproductive system, although its precise role in this regard remains unclear. We have hypothesized that IGF signaling is required for embryonic germline development, which requires the specification and proliferation of primordial germ cells (PGCs) in an extragonadal location, followed by directed migration to the genital ridges. We tested this hypothesis using loss-of-function studies in the zebrafish embryo, which possesses two functional copies of the Type-1 IGF receptor gene (igf1ra, igf1rb). Knockdown of IGF1Rb by morpholino oligonucleotides (MO) results in mismigration and elimination of primordial germ cells (PGCs), resulting in fewer PGCs colonizing the genital ridges. In contrast, knockdown of IGF1Ra has no effect on PGC migration or number despite inducing widespread somatic cell apoptosis. Ablation of both receptors, using combined MO injections or overexpression of a dominant-negative IGF1R, yields embryos with a PGC-deficient phenotype similar to IGF1Rb knockdown. TUNEL analyses revealed that mismigrated PGCs in IGF1Rb-deficient embryos are eliminated by apoptosis; overexpression of an antiapoptotic gene (Bcl2l) rescues ectopic PGCs from apoptosis but fails to rescue migration defects. Lastly, we show that suppression of IGF signaling leads to quantitative changes in the expression of genes encoding CXCL-family chemokine ligands and receptors involved in PGC migration. Collectively, these data suggest a novel role for IGF signaling in early germline development, potentially via cross-talk with chemokine signaling pathways.
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PMID:Insulin-like growth factor receptor 1b is required for zebrafish primordial germ cell migration and survival. 1736 6

Identification of genes/proteins that are differentially expressed in HER2 (erbB-2) oncogene-dependent breast carcinomas is essential in elucidating the mechanistic basis of their increased metastastic potential and resistance to several anti-cancer therapies. We here applied human cytokine antibody arrays with the goal of identifying a unique HER2-induced 'cytokine signature' in breast cancer. Human Cytokine Array III (RayBiotech, Inc.), which simultaneously detects 42 cytokines and growth factors on one membrane, was used to determine the profile of cytokines in conditioned media obtained from MCF-7/Her2-18 cells, a MCF-7-derived clone engineered to stably express the full-length human HER2 cDNA controlled by a SV40 viral promoter, and from the MCF-7/neo control sub-line. We identified two inflammatory and pro-angiogenic CXC chemokines with at least a 10-fold increased expression in HER2-overexpressing MCF-7/Her2-18 transfectants when compared to matched control MCF-7/neo cells: CXCL8 (IL-8; Interleukin-8) and CXCL1 and (GRO; Growth-related oncogene). HER2-induced differential overexpression of IL-8 and GRO was validated by ELISA and further confirmed by switching off the HER2 signalling. Treatment with the tyrosine kinase inhibitor gefitinib (Iressa) returned the expression levels of IL-8 and GRO back to the baseline observed in MCF-7 breast cancer cells, which express physiological levels of HER2. To evaluate the diagnostic utility of these findings, cytokine-specific antibody arrays were incubated with sera retrospectively collected from metastatic breast cancer patients. This approach revealed a high similarity between the 'cytokine signature' observed in serum samples and that obtained in media conditioned by breast cancer-derived cell lines. Thus, IL-8 and GRO circulating levels were significantly higher in HER2-positive breast cancer patients compared with HER2-negative patients. These findings reveal for the first time that: a) Enhanced synthesis and secretion of members of the IL-8/GRO chemokine family, which have recently been linked to oestrogen receptor (ER) inaction, increased cell invasion and angiogenesis, may represent a new pathway involved in the metastatic progression and endocrine resistance of HER2-overexpressing breast carcinomas, and b) Circulating levels of IL-8 and GRO cytokines may represent novel biomarkers monitoring breast cancer responses to endocrine treatments and/or HER2-targeted therapies.
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PMID:Protein array technology to detect HER2 (erbB-2)-induced 'cytokine signature' in breast cancer. 1737 3

The present article shows that a short-term exposure of purified human neutrophils to recombinant insulin conferred on these cells both the ability to migrate and the capacity to mobilize [Ca2+]i in response to CCL3, a chemokine per se ineffective with native neutrophils. Furthermore, the effects of recombinant insulin were reproduced by short-term incubation with sera from adult patients with metabolic syndrome, known to be characterized by a hyperinsulinemic state. A strict linear correlation (P<0.01) between sera insulin levels and sera's ability to induce neutrophil locomotion was indeed found. Our data also suggest that (i) insulin primed neutrophils for migration to CCL3 via the selective activation of JNK 1/2, as shown by the use of inhibitors and kinase activation assay; (ii) the activation of Src kinases was necessary but not sufficient for CCL3-induced locomotory activity; (iii) PI3K-Akt, ERK 1/2, and p38 MAPK were not involved in insulin-induced migratory competence. In summary, we provided evidence that the exposition of neutrophils to insulin, as it occurs in hyperinsulinemic conditions, confers the competence of the cells to migrate in response to CCL3, known to be generated near atherosclerotic plaques. As neutrophils have been recently suggested to be involved in breaking unstable atherosclerotic plaques, the present findings contribute to the understanding of the pathophysiology of plaque instability. Finally, biochemical analysis herein carried out raises the hypothesis of JNK 1/2 as an attractive therapeutic target.
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PMID:Insulin primes human neutrophils for CCL3-induced migration: crucial role for JNK 1/2. 1738 84

9-cis-Retinoic acid (9CRA) plays an important role in the immune response; this includes cytokine production and cell migration. We have previously demonstrated that 9CRA increases expression of chemokine receptors CCR1 and CCR2 in human monocytes. To better understand how 9CRA induces CCR1 and CCR2 expression, we examined the contribution of signaling proteins in human monocytic THP-1 cells. The mRNA and surface protein up-regulation of CCR1 and CCR2 in 9CRA-stimulated cells were weakly blocked by the pretreatment of SB202190, a p38 MAPK inhibitor, and PD98059, an upstream ERK inhibitor. Activation of p38 MAPK and ERK1/2 was induced in both a time and dose-dependent manner after 9CRA stimulation. Both p38 MAPK and ERK1/2 phosphorylation peaked at 2 h after a 100 nM 9CRA treatment. 9CRA increased calcium influx and chemotactic activity in response to CCR1-dependent chemokines, Lkn-1/CCL15, MIP-1alpha/CCL3, and RANTES/CCL5, and the CCR2-specific chemokine, MCP-1/CCL2. Both SB202190 and PD98059 pretreatment diminished the increased calcium mobilization and chemotactic ability due to 9CRA. SB202190 inhibited the expression and functional activities of CCR1 and CCR2 more effectively than did PD98059. Therefore, our results demonstrate that 9CRA transduces the signal through p38 MAPK and ERK1/2 for CCR1 and CCR2 up-regulation, and may regulate the pro-inflammatory process through the p38 MAPK and ERK-dependent signaling pathways.
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PMID:p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells. 1746 74

Cigarette smoking, a major risk factor for chronic obstructive pulmonary disease, can cause airway inflammation, airway narrowing, and loss of elasticity, leading to chronic airflow limitation. In this report, we sought to define the signaling pathways activated by smoke and to identify molecules responsible for cigarette smoke-induced inflammation. We applied cigarette smoke water extract (CSE) to primary human lung fibroblasts and found that CSE significantly increased CXC chemokine IL-8 production. Meanwhile, 70-kDa heat shock protein (HSP70) was also induced by CSE in a dose- and time-dependent manner. CSE treatment stimulated HSP70 secretion by primary fibroblasts, which augmented IL-8 production. This was further confirmed by exogenously added recombinant HSP70. Using HSP70 small interfering RNA, we confirmed that CSE-induced chemokine production was dependent on heat shock protein expression. Further investigation showed that CSE could also stimulate early growth response-1 (EGR-1) in an ERK-dependent manner and that the expression of HSP70 was EGR-1 dependent. In view of these findings, we hypothesize that the MAPK-EGR-1-HSP70 pathway regulates the cigarette smoke-induced inflammatory process.
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PMID:MAPK pathway mediates EGR-1-HSP70-dependent cigarette smoke-induced chemokine production. 1749 53

Chemokines are small, secreted proteins and are now the largest known cytokine family. They mediate their effects through a family of G-protein-coupled receptors and were initially recognized for their ability to act as chemo-attractants and activators of specific types of leucocytes in a variety of immune and inflammatory responses. However, during the past 5 years there has been a chemokine revolution in cancer and all scientists and clinicians in oncology-related fields are now aware of their crucial role at all stages of neoplastic transformation and progression. The most important chemokine ligand-receptor interaction is that of the CXCL12 (stromal cell-derived factor-1, SDF-1) ligand with its exclusive receptor CXCR4; this interaction has a pivotal role in the directional migration of cancer cells during the metastatic process. This has been demonstrated by in vitro and in vivo experiments in addition to retrospective clinical studies. These findings have exciting implications in the field of cancer therapeutics, with several small molecule CXCR4 antagonists having been developed, which may provide clinical benefit in the therapy of cancer metastasis. Interestingly, it is likely that the effect of the anti-HER2 antibody [trastuzumab (Herceptin] in breast cancer involves downregulation of the CXCR4 receptor. Unfortunately, a major problem is that chemokine receptors are expressed in other cells within the body, particularly those of the immune system and it is not clear what effects long-term CXCR4 antagonism could have on innate and adaptive immunity. However, there is little doubt that the great strides made in elucidating the complex relationship between chemokines and their role in cancer will soon translate into significant survival benefits for patients.
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PMID:Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration. 1751 May 63


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