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)

In adult testis, telomerase activity is exclusively detectable during the early steps of spermatogenesis and is downregulated during differentiation to spermatozoa. Knowledge about telomerase activity during testis development from birth to adulthood is still scarce. Telomerase activity is regulated primarily via the transcriptional initiation of TERT expression which encodes its catalytic subunit. We used the hTERTp-lacZ transgenic mouse model that expresses the bacterial lacZ reporter gene under the control of an 8.0-kbp human TERT promoter fragment to analyze simultaneously endogenous mouse Tert gene expression as well as human TERT promoter activity during mouse testis development. We show that human TERT promoter activity increased during puberty and was highest in adult mouse testis whereas mouse Tert expression and telomerase activity were found to be high in testis from the earliest time point tested (6 days postpartum). Histological analysis revealed that beta-galactosidase expression, encoded by the lacZ reporter gene, is present in all seminiferous tubules in adult testis, but in a subset of tubules before puberty. We further analyzed the expression of SCF/ c-KIT, which was described to regulate spermatogonia proliferation and mouse Tert expression, in prepubertal and adult testis by immunohistochemistry. Whereas SCF and c-KIT were detectable in all seminiferous tubules, a spatial and preclusive expression pattern of human TERT promoter activity and activated c-KIT (p-c-KIT Tyr 567/569) was observed in prepubertal testes.
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PMID:Differential regulation of human and mouse telomerase reverse transcriptase (TERT) promoter activity during testis development. 1872 84

It is known that UV modulates the expression of paracrine factors that regulate melanocyte function in the skin. We investigated the consequences of repetitive UV exposure of human skin in biopsies of 10 subjects with phototypes 2-3.5 taken 1-4 years later. The expression of melanogenic factors (TYR, MART1, MITF), growth factors/receptors (SCF/KIT, bFGF/FGFR1, ET1/EDNRB, HGF, GM-CSF), adhesion molecules (beta-catenin, E-cadherin, N-cadherin), cell cycle proteins (PCNA, cyclins D1, E2) as well as Bcl-2, DKK1, and DKK3, were analyzed by immunohistochemistry. Most of those markers showed no detectable changes at > or = 1 year after the repetitive UV irradiation. Although increased expression of EDNRB protein was detected in 3 of 10 UV-irradiated subjects, there was no detectable change in the expression of ET1 protein or in EDNRB mRNA levels. In summary, only the expression of TYR, MART1, and/or EDNRB, and only in some subjects, was elevated at > or = 1 year after UV irradiation. Thus the long-term effects of repetitive UV irradiation on human skin did not lead to significant changes in skin morphology and there is considerable subject-to-subject variation in responses. The possibility that changes in the expression and function of EDNRB triggers downstream activation of abnormal melanocyte proliferation and differentiation deserves further investigation.
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PMID:Long-lasting molecular changes in human skin after repetitive in situ UV irradiation. 1894 95

Transcription of the mast cell growth factor SCF (stem cell factor) is upregulated in inflammatory conditions, and this is dependent upon NF-kappaB, as well as the MAP kinases p38 and ERK activation. We show here that the MAPK downstream nuclear kinase MSK1 induces NF-kappaB p65 Ser276 phosphorylation upon IL-1beta treatment, which was inhibited in cells transfected with a MSK1 kinase-dead (KD) mutant compared to the WT control. In addition, we show by ChIP experiments that MSK1 as well as MAPK inhibition abolishes binding of p65, of its coactivator CBP, and of MSK1 itself to the kappaB intronic enhancer site of the SCF gene. We show that interaction between NF-kappaB and CBP is prevented in cells transfected by a p65 S276C mutant. Finally, we demonstrate that both transfections of MSK1-KD and MSK1 siRNA -- but not the WT MSK1 or control siRNA -- downregulate the expression of SCF induced by IL-1ss. Our study provides therefore a direct link between MSK1-mediated phosphorylation of Ser276 p65 of NF-kappaB, allowing its binding to the SCF intronic enhancer, and pathophysiological SCF expression in inflammation.
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PMID:Ser276 phosphorylation of NF-kB p65 by MSK1 controls SCF expression in inflammation. 1919 68

The receptor tyrosine kinase MET is a major component controlling the invasive growth program in embryonic development and in invasive malignancies. The discovery of therapeutic antibodies against MET has been difficult, and antibodies that compete with hepatocyte growth factor (HGF) act as agonists. By applying phage technology and cell-based panning strategies, we discovered two fully human antibodies against MET (R13 and R28), which synergistically inhibit HGF binding to MET and elicit antibody-dependent cellular cytotoxicity. Cell-based phosphorylation assays demonstrate that R13 and R28 abrogate HGF-induced activation of MET, AKT1, ERK1/2, and HGF-induced migration and proliferation. FACS experiments suggest that the inhibitory effect is mediated by "locking" MET receptor in a state with R13, which then increases avidity of R28 for the extracellular domain of MET, thus blocking HGF binding without activating the receptor. In vivo studies demonstrate that the combination of R13/28 significantly inhibited tumor growth in various colon tumor xenograft models. Inhibition of tumor growth was associated with induction of hypoxia. Global gene expression analysis shows that inhibition of HGF/MET pathway significantly upregulated the tumor suppressors KLF6, CEACAM1, and BMP2, the negative regulator of phosphatidylinositol-3-OH-kinase PIK3IP1, and significantly suppressed SCF and SERPINE2, both enhancers of proliferation and invasiveness. Moreover, in an experimental metastasis model, R13/28 increased survival by preventing the recurrence of otherwise lethal lung metastases. Taken together, these results underscore the utility of a dual-antibody approach for targeting MET and possibly other receptor tyrosine kinases. Our approach could be expanded to drug discovery efforts against other cell surface proteins.
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PMID:Discovery of fully human anti-MET monoclonal antibodies with antitumor activity against colon cancer tumor models in vivo. 1930 90

The development of a lentiviral system to deliver genes to specific cell types could improve the safety and the efficacy of gene delivery. Previously, we have developed an efficient method to target lentivectors to specific cells via an antibody-antigen interaction in vitro and in vivo. We report herein a targeted lentivector that harnesses the natural ligand-receptor recognition mechanism for targeted modification of c-KIT receptor-expressing cells. For targeting, we incorporate membrane-bound human stem cell factor (hSCF), and for fusion, a Sindbis virus-derived fusogenic molecule (FM) onto the lentiviral surface. These engineered vectors can recognize cells expressing surface CD117, resulting in efficient targeted transduction of cells in an SCF-receptor dependent manner in vitro, and in vivo in xenografted mouse models. This study expands the ability of targeting lentivectors beyond antibody targets to include cell-specific surface receptors. Development of a high titer lentivector to receptor-specific cells is an attractive approach to restrict gene expression and could potentially ensure therapeutic effects in the desired cells while limiting side effects caused by gene expression in non-target cells.
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PMID:Targeted gene delivery to CD117-expressing cells in vivo with lentiviral vectors co-displaying stem cell factor and a fusogenic molecule. 1945

Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl(-/-) haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl(+/+) HSPCs, and transduction of C-CBL mutants into c-Cbl(-/-) HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl(+/+) background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.
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PMID:Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. 1967 35

In order to investigate the effect of anti-TGF-beta1 monoclonal antibody on the expansion of cord blood CD34(+) cells, the purified cord blood CD34(+) cells were divided into three groups: blank control group: purified cord blood CD34(+) cells cultured on day 0; control group: cells cultured for 3 days in the culture system, containing SCF, IL-3, IL-6 and FLT3-L; test group: cells cultured for 3 days in the same culture system as control group, but with anti-TGF-beta1 monoclonal antibody. The mononuclear cell counting (MNC), the expression of CD34 and c-kit, and CFU-GEMM, BFU-E and CFU-GM counting were detected in all three groups. The result showed that the expansion of MNCs, CD34(+) cells and CD34(+)c-kit(+) cells in test group [(2.35 +/- 0.25) x 10(5), (1.16 +/- 0.29) x 10(5), (1.09 +/- 0.26) x 10(5)] was significantly higher than that in control group [(1.25 +/- 0.13) x 10(5), (0.55 +/- 0.19) x 10(5), (0.51 +/- 0.2) x 10(5)](p < 0.01). The expansion of more primitive CD34(+)c-kit(-) subpopulation in test group [(12.95 +/- 3.17) x 10(3)] was even significantly higher than in control group (1.71 +/- 0.83) x 10(3) (p < 0.01). Colony forming assay showed that the number of earlier progenitor colony CFU-GEMM, BFU-E in test group [(16.3 +/- 4.72) x 10(3), (60.5 +/- 20.96) x 10(3)] was higher than that in control group [(5.0 +/- 2.58) x 10(3), (16.25 +/- 7.93) x 10(3)] (p < 0.01). The number of relatively mature CFU-GM between test group and control group was not statistical significance [(6.33 +/- 2.85) x 10(3) vs (4.0 +/- 2.28) x 10(3)](p > 0.05), but both were higher than that in blank group (0.75 +/- 0.29) x 10(3). These results demonstrated that anti-TGF-beta1 monoclonal antibody promoted the expansion of MNC and CD34(+) cells, and even more marked expansion of the more primitive progenitor cells-CD34(+)c-kit(-) cells. Meanwhile, it enhanced the output of more immature colony CFU-GEMM and BFU-E, but had no evident influence on the mature myeloid colony CFU-GM. It is concluded that the anti-TGF-beta1 monoclonal antibody can synergize other cytokines to enhance the proliferation of cord blood CD34(+) progenitor cells effectively, and it is more important that can reserve more primitive progenitor cells.
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PMID:[Effects of anti-TGF-beta1 monoclonal antibody on in vitro expansion of cord blood CD34(+) cells]. 2003 Sep 44

There is an on-going need to identify medications suitable for the long-term treatment of canine atopic dermatitis (CAD). Masitinib mesilate is a potent and selective tyrosine kinase inhibitor of the c-KIT receptor. A strong relationship exists between the SCF/c-KIT pathway and pathogenesis of CAD, suggesting that masitinib may potentially fulfil the above role. This study reports on an uncontrolled pilot study of masitinib in CAD. Masitinib was administered orally to 11 dogs at a mean dose of 11.0 +/- 1.83 mg/kg/day (free base) for 28 days. Treatment response was assessed by evolution of clinical appearance according to a modified version of the Canine Atopic Dermatitis Extent and Severity Index (mCADESI), pruritus scale and surface area of lesions. Masitinib improved CAD with a mean reduction in mCADESI of 50.7 +/- 29.8% (95% C.I. = 29.4-72.0; p = 0.0004) at day 28 relative to baseline, with 8/10, 8/10 and 4/10 dogs showing improvement of >or=33%, >or=40% and >or=50%, respectively. Improvement was further evidenced by a decrease in pruritus score and the surface area of lesions. No serious or severe adverse events occurred during this trial, although 6/11 dogs presented with mild to moderate treatment related adverse events. There is sufficient compelling evidence to warrant further investigation.
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PMID:Masitinib for the treatment of canine atopic dermatitis: a pilot study. 2003 87

FES is a cytoplasmic tyrosine kinase activated by several membrane receptors, originally identified as a viral oncogene product. We have recently identified FES as a crucial effector of oncogenic KIT mutant receptor. However, FES implication in wild-type KIT receptor function was not addressed. We report here that FES interacts with KIT and is phosphorylated following activation by its ligand SCF. Unlike in the context of oncogenic KIT mutant, FES is not involved in wild-type KIT proliferation signal, or in cell adhesion. Instead, FES is required for SCF-induced chemotaxis. In conclusion, FES kinase is a mediator of wild-type KIT signalling implicated in cell migration.
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PMID:FES kinase participates in KIT-ligand induced chemotaxis. 2011 79

The paracrine networks of the human melanoma microenvironment are able to influence tumor growth and progression. Among the paracrine growth factors involved in skin homeostasis, the KGF/FGF7 secreted by dermal fibroblasts promotes the epidermal proliferation and differentiation as well as the release from keratinocytes of other paracrine mediators. To evaluate the possible role played by KGF in affecting the behavior of different subtypes of melanoma carrying activating mutations or overexpression of the SCF receptor c-KIT, we used human melanoma cell lines, characterized by different expression levels of c-KIT and opposing responsivity to SCF, and HaCaT keratinocytes. Quantitative real-time reverse transcription-polymerase chain reaction assay and ELISA test on KGF-treated keratinocytes showed enhanced expression and secretion of SCF in response to KGF and dependent on functional KGF receptor. Immunofluorescence microscopy and biochemical analysis showed, in one of the selected melanoma cell models, SCF-dependent c-KIT activation induced by stimulation with the culture supernatants collected from KGF-treated keratinocytes. In keratinocyte-melanoma cocultures stained for the Ki67 proliferation marker, incubation with KGF induced enhanced growth not only of the keratinocytes but also of the melanoma cells, which could be blocked by the c-KIT inhibitor imatinib, demonstrating the establishment of a KGF-induced paracrine signaling network owing to the coexpression of biologically active SCF released from keratinocytes and functional c-KIT on melanoma cells.
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PMID:KGF Promotes Paracrine Activation of the SCF/c-KIT Axis from Human Keratinocytes to Melanoma Cells. 2036 Sep 32


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