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)

Despite the progress in cancer therapeutics and chemotherapy development with the introduction of new drugs, advanced gastric cancer continues to have an extremely poor prognosis and with limited treatment options. The introduction of new antitarget drugs has introduced a new perspective in cancer treatment in general and gastric cancer in particular. Nevertheless, few studies have been developed with this generation of drugs. The monoclonal antibody antiepidermal growth factor receptor (EGFR) cetuximab and the antiangiogenic bevacizumab have been used in phase I and II studies with good results, which need to be confirmed in new phase III studies. The carcinogenesis of this tumor provides information regarding two transcription and signaling pathways of great interest and with therapeutic potential. Infection by Helicobacter pylori is recognized as the cause of gastric cancer development, and there are two elements that play an important role in this process: the CagA gene, whose protein is introduced in the cell by H. pylori initiates the process; and the hedgehog signaling pathway, which regulates the gastric mucosa and is very frequently activated in gastric cancer. Taking action on these agents may be a new and effective method of treating gastric cancer, and therefore must be researched.
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PMID:New drugs in the treatment of gastric tumors. 1849 Feb 41

Infection with hepatitis C virus (HCV) is still a major public health problem, and the events leading to hepatocyte infection are not yet fully understood. Combining confocal microscopy with biochemical analysis and studies of infection requirements using pharmacological inhibitors and small interfering RNAs, we show here that engagement of CD81 activates the Rho GTPase family members Rac, Rho, and Cdc42 and that the block of these signaling pathways drastically reduces HCV infectivity. Activation of Rho GTPases mediates actin-dependent relocalization of the HCV E2/CD81 complex to cell-cell contact areas where CD81 comes into contact with the tight-junction proteins occludin, ZO-1, and claudin-1, which was recently described as an HCV coreceptor. Finally, we show that CD81 engagement activates the Raf/MEK/ERK signaling cascade and that this pathway affects postentry events of the virus life cycle. In conclusion, we describe a range of cellular events that are manipulated by HCV to coordinate interactions with its multiple coreceptors and to establish productive infections and find that CD81 is a central regulator of these events.
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PMID:CD81 is a central regulator of cellular events required for hepatitis C virus infection of human hepatocytes. 1857 6

Chlamydia are obligate intracellular bacteria that cause variety of human diseases. Host cells infected with Chlamydia are protected against many different apoptotic stimuli. The induction of apoptosis resistance is thought to be an important immune escape mechanism allowing Chlamydia to replicate inside the host cell. Infection with C. trachomatis activates the Raf/MEK/ERK pathway and the PI3K/AKT pathway. Here we show that inhibition of these two pathways by chemical inhibitors sensitized C. trachomatis infected cells to granzyme B-mediated cell death. Infection leads to the Raf/MEK/ERK-mediated up-regulation and PI3K-dependent stabilization of the anti-apoptotic Bcl-2 family member Mcl-1. Consistently, interfering with Mcl-1 up-regulation sensitized infected cells for apoptosis induced via the TNF receptor, DNA damage, granzyme B and stress. Our data suggest that Mcl-1 up-regulation is primarily required to maintain apoptosis resistance in C. trachomatis-infected cells.
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PMID:Mcl-1 is a key regulator of apoptosis resistance in Chlamydia trachomatis-infected cells. 1876 17

Infection of macrophages with Leishmania parasites does not result in the production of IL-12. In addition, infection with Leishmania suppresses IL-12 production elicited by otherwise potent activators of IL-12. We provide evidence that engagement of phosphatidyl inositol-3 kinase (PI3K) signaling during Leishmania amazonensis infection leads to the prevention of IL-12 p70 production at the level of transcription of its p40 subunit in bone marrow derived macrophages (BMDMPhi). Inhibition of PI3K signaling with specific inhibitors of PI3K or the downstream kinase Akt, reverses the IL-12 blockade. Although the MAP kinase ERK (p44 and p42) was transiently activated by infection with L. amazonensis, inhibition of MEK, the kinase upstream of ERK, with PD98059, did not reverse the blockade of IL-12. Furthermore, inhibition of the other MAP kinases JNK and p38 as well as treatment of cells with pertussis toxin that blocks G protein mediated signaling, did not reverse the prevention of IL-12 production by Leishmania infection. Interestingly, activation of PI3K/Akt signaling had differential effects on ERK and p38 activation. Taken together we propose that infection of BMDMPhi with Leishmania promastigotes activates both positive and negative signaling pathways that control IL-12 production. PI3K signaling activated by the infection is the negative signaling pathway that prevents IL-12 production.
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PMID:Activation of PI3K/Akt signaling has a dominant negative effect on IL-12 production by macrophages infected with Leishmania amazonensis promastigotes. 1918 78

The purpose of this study is to describe the types of injuries and surgical treatments associated with open knee dislocations and to present the functional outcomes of these patients. Between 2001 and 2005, the medical records of patients that sustained traumatic open knee dislocations at our Level 1 Trauma Center were retrospectively reviewed. Initial surgical intervention was performed in all patients including placement of spanning external fixator, repair of vascular injuries if necessary, and irrigation and debridement of the open wounds. Ligamentous reconstruction was delayed until after limb salvage. The Short Form-12 was the primary outcome measure. Seven patients (five male, two female) had a mean age of 31.9 years (range 22-44) at the time of injury (five right, two left). Motorcycle accident was the most common cause (57%). Follow-up was a mean 27.6 months. The PCL was damaged in all patients. Three patients underwent angiography for absent/diminished pulses on initial exam with two requiring operative intervention. Three patients had associated common peroneal nerve injury (one iatrogenic). Ten (10.7) operative procedures were performed per patient (range 5-18) with an average of 6.6 debridements (range 2-11). Infection rate was 43% with one patient undergoing amputation for infection. Good to excellent results were found in 33% of patients. Most patients (86%) report some residual symptomatic or functional deficit. Due to the injury complexity in open traumatic knee dislocations, the surgical treatment is extensive and challenging. While infection rates are high, aggressive, individualized treatment can lead to satisfactory outcome although full return to activity is difficult to achieve using current treatment methods.
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PMID:Surgical outcomes after traumatic open knee dislocation. 1920 64

Human rhinovirus (HRV) infections can trigger exacerbations of lower airway diseases. Infection of airway epithelial cells induces production of a number of proinflammatory chemokines that may exacerbate airway inflammation, including CXCL10, a chemoattractant for type 1 lymphocytes and NK cells. Primary human bronchial epithelial cells and the BEAS-2B human bronchial epithelial cell line were used to examine the role of MAPK pathways in HRV-16-induced production of CXCL10. Surprisingly, PD98059 and U0126, two inhibitors of the MEK1/2-ERK MAPK pathway, significantly enhanced HRV-16-induced CXCL10 mRNA and protein. This enhancement was not seen with IFN-beta-induced production of CXCL10. Studies using small interfering RNA revealed that knockdown of MEK1, but not MEK2, was associated with enhanced HRV-induced CXCL10 production. Promoter construct studies revealed that PD98059 and U0126 enhanced HRV-16-induced transcriptional activation of CXCL10. HRV-16-induced promoter activation was regulated by two NF-kappaB binding sites, kappaB1 and kappaB2, and by an IFN-stimulated response element. Inhibitors of the MEK1/2-ERK pathway did not alter HRV-16-induced activation of tandem repeat kappaB1 or kappaB2 constructs, nor did they alter HRV-16-induced nuclear translocation/binding of NF-kappaB to either kappaB1 or kappaB2 recognition sequences. Furthermore, PD98059 and U0126 did not alter phosphorylation or degradation of IkappaBalpha. In contrast, inhibitors of the MEK1/2-ERK pathway, and small interfering RNA knockdown of MEK1, enhanced nuclear translocation/binding of IFN regulatory factor (IRF)-1 to the IFN-stimulated response element recognition sequence in HRV-16 infected cells. We conclude that activation of MEK1 selectively down-regulates HRV-16-induced expression of CXCL10 via modulation of IRF-1 interactions with the gene promoter in human airway epithelial cells.
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PMID:Selective transcriptional down-regulation of human rhinovirus-induced production of CXCL10 from airway epithelial cells via the MEK1 pathway. 1934 64

Infection with human T-cell leukemia virus type 1 (HTLV-1) leads sometimes to the development of adult T-cell lymphoma/leukemia (ATL), which is invariably fatal and often associated with humoral hypercalcemia of malignancy. The transformation of infected CD4 T cells and the pathogenesis of leukemia have been studied with great limitation in tissue culture and patients. To better understand the pathogenesis and perform preclinical drug studies, animal models of ATL are urgently needed. In mice, inoculation of HTLV-1 cell lines mostly leads to development of localized lymphomas. To develop an ATL animal model with leukemic spread of ATL cells, mouse strains with different well-defined immune deficiencies were inoculated intraperitoneally with different HTLV-1-infected cell lines (ACH.2, C8166, MT-2, MET-1). Inoculation of MET-1 cells into NOD/SCID mice provided the best model system for slowly developing T-cell leukemia with multiple organ involvement. In leukemic mice, an increase in serum calcium levels correlated with expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand on leukemic cells and secretion of parathyroid hormone-related protein and interleukin-6. In contrast to the other cell lines that did not spread systemically, MET-1 expressed both the adhesion molecules CD11a (LFA-1alpha) and CD49d (VLA-4alpha) and produced or induced expression of matrix metalloproteinases 1, 2, 3, and 9, thus underlining the importance of these molecules in the spread of adult T-cell leukemia cells. The MET-1/NOD/SCID model will be useful for developing interventions against invasion and spread of leukemic cells and subsequent humoral hypercalcemia of malignancy.
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PMID:Expression of tumor invasion factors determines systemic engraftment and induction of humoral hypercalcemia in a mouse model of adult T-cell leukemia. 1942 77

Prostate cancer tumor growth and neovascularization is promoted by an interplay between migratory tumor stromal cells such as specialized tumor-associated macrophages (TAMs) and circulating endothelial precursor cells (CEPs). As vehicles for tumor therapy, human CEPs are relatively easy to isolate from peripheral blood, are able to proliferate long-term in vitro, are amenable to viral manipulation, and preferentially home to regions of ischemia found in growing tumors. We show here that human peripheral blood CEPs expanded ex vivo migrate to prostate cancer cells in vitro and efficiently home to human prostate tumor xenografts in vivo. Infection of precursors ex vivo with an adenovirus constructed to secrete a soluble form of the colony-stimulating factor-1 receptor CD115 that inhibits macrophage viability and migration in vitro significantly decreases the number of TAMs in xenografts (p < .05), reduces proliferation (p < .01) and vascular density (p < .03), and suppresses the growth of xenografts (p < .03). These data show for the first time that targeting stromal cell processes with cellular therapy has the potential to retard prostate tumor growth.
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PMID:Adenoviral-mediated endothelial precursor cell delivery of soluble CD115 suppresses human prostate cancer xenograft growth in mice. 1952 14

Infection of macrophages with Mycobacterium tuberculosis (Mtb) induces cell death by apoptosis or necrosis. TLRs 2 and 4 recognition of mycobacterial ligands has been independently associated to apoptosis induction. To try to understand the particular contribution of these receptors to apoptotic or necrotic signaling upon infection with live Mtb H37Rv, we used macrophage lines derived from wild-type or TLR2-, TLR4-, and MyD88-deficient mouse strains. Mtb-infection triggered apoptosis depending on a TLR2/TLR4/MyD88/p38/ERK/PI-3K/NF-kB pathway; however, necrosis was favored in absence of TLR4 signaling independently of p38, ERK1/2, PI-3K or NF-kappaB activity. In conclusion, our results indicate that cooperation between TLR2- and TLR4-dependent mediated signals play a critical role in macrophage apoptosis induced by Mtb and the TLR4-mediated signaling has important role in the maintenance of the balance between apoptotic vs. necrotic cell death induced by macrophage infection with Mtb.
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PMID:Role of TLR2- and TLR4-mediated signaling in Mycobacterium tuberculosis-induced macrophage death. 1991 59

Studies from our laboratory and those of others have implicated lipopolysaccharide (LPS)-induced MAPK signaling as an important pathway in the regulation of cytokine expression. In this article, the regulation of IL-12 expression in two different human myeloid cell populations was evaluated. In primary monocytes, the inhibition of p38 enhanced IL-12 production, whereas it downregulated IL-12 production in THP-1 cells. The role of MAPK signaling in transcription factor binding to the IL-12p40 promoter was subsequently determined. In primary monocytes, ERK and p38 inhibition increased binding of AP-1 and Sp1, respectively, to the IL-12p40 promoter, while JNK inhibition increased NF-kappaB, AP-1, and Sp1 binding. In THP-1 cells, p38, ERK, and JNK inhibition increased NF-kappaB and Sp1 binding to the IL-12p40 promoter, while inhibiting AP-1 binding. In monocytes, mutations in the NF-kappaB, AP-1, Sp1, or Ets-2 binding sites resulted in complete inhibition of LPS-stimulated IL-12p40 promoter activity using a luciferase-based assay. In contrast, promoter activity was abrogated in THP-1 cells only when the Sp1 or Ets-2 binding sites were mutated. Transcription factor binding to the IL-12p40 promoter following in-vitro HIV infection demonstrated several differences between monocytes and THP-1 cells. Infection with HIV produced an increase in NF-kappaB, AP-1, and Sp1 binding in primary monocytes. In contrast, binding of Ets-2 was dramatically impaired following HIV infection of monocytes, but was unaffected in THP-1 cells. These data clearly show that although LPS induces IL-12p40 expression in primary monocytes and THP-1 cells, the signaling pathways involved and the effect of HIV infection differ and can have disparate effects in these two cell types.
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PMID:Disparate regulation of LPS-induced MAPK signaling and IL-12p40 expression between different myeloid cell types with and without HIV infection. 2012 99


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