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)

The biological effects of flt3-L, and the expression of its tyrosine kinase receptor (flt3, CD135) were investigated on the immature subsets of human circulating peripheral blood progenitors obtained from cancer patients or normal volunteer donors, after mobilization with rhG-CSF or chemotherapy. flt3 was expressed at low levels, and its expression increased concomitantly with expression of CD38 within the CD34+ cell population. Despite this low-level expression, flt3-L exerted synergistic effects with a combination of c-kit ligand, IL-3, IL-6, GM-CSF and G-CSF, mainly to induce proliferation of CD34+/CD38- cells. In addition, flt3-L increased the detection of HPP-CFC, both immediately after cell selection, and after 7 and 14 d of cultures. We conclude that flt3-L is active on circulating early mobilized haemopoietic progenitors, despite the low- level expression of its receptor.
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PMID:Early progenitor cells from human mobilized peripheral blood express low levels of the flt3 receptor, but exhibit various biological responses to flt3-L. 1046 May 91

Dendritic cells (DC) are professional antigen presenting cells (APC) whose proliferation and functional differentiation can be induced by hematopoietic growth factors including GM-CSF and FLT3 ligand (FL). Colorectal cancers are known to be infiltrated by dendritic cells (DC) and neoplastic cells have been shown to produce GM-CSF. In this work we investigated FLT3 ligand (FL) gene expression and protein production in human colorectal cancer cell lines and clinical tumor specimens. Using reverse transcription polymerase chain reaction (RT-PCR), 6 out of 6 established tumor lines were found to express to variable extents FL gene. In 1 of them, SW480, FL immunoreactivity could be observed by taking advantage of specific antibodies. In contrast, soluble FL could not be detected in any culture supernatant. FLT3 receptor (FR) gene was not expressed and exogenous addition to the cultures of recombinant FL (rFL) did not affect the proliferation of the tumor lines. FL gene expression was investigated using a densitometry-assisted, semiquantitative RT-PCR in clinical tumor specimens. Specific FL gene transcripts were amplified from 12 of 12 surgical samples. In these cases, FL gene expression of significantly lower intensity was also detected in healthy mucosa sampled in the vicinity (2 cm) or at a distance (10 cm) from neoplastic outgrowth. Immunohistochemical studies identified FL-positive cancer cells in 5 of 5 cases tested. No positivity was detected in healthy mucosa epithelia at a distance from the tumor or in stromal cells. FL content in preoperative sera from colorectal cancer patients (n = 13) did not exceed the levels detected in healthy donors (</= 100 pg/ml).
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PMID:FLT3 ligand gene expression and protein production in human colorectal cancer cell lines and clinical tumor specimens. 1073 51

The appearance of blasts in acute myeloid leukemia (AML) reflects a shift from cellular processes inducing maturation and cell death to those favouring survival and accumulation. We have monitored changes in the growth factor signalling molecule MAPKinase, in the cytoprotective protein Bcl-2 and in the cell death protein Bax, during maturation of proliferating and non-proliferating AML blasts in vitro. Eighteen AML samples were cultured for 7 d in serum-free medium with or without a supplement of recombinant cytokines comprising c-kit ligand, IL3 and GMCSF. Maturation of AML blasts, as assessed by morphology on Romanowsky-stained slides of 7/18 samples and by changes in surface CD markers on all 18 leukemias, occurred in both the absence and presence of cytokines. Cell numbers decreased to a mean of 71% after 7 d of cytokine-free culture, but increased to 210% in cytokine-supplemented cultures. The proportion of CD15-positive cells, assessed by flow cytometry, increased over 7 d in 17/18 samples, from a mean of 22% to 68% in cytokine-free cultures and to 72% in cytokine-supplemented cultures (p = < 0.0001 for both). By immunofluorescence/flow cytometry, there was no significant change in Bcl-2 over 7 d of culture, while Bax increased, particularly in cytokine-free cultures (2.2-fold), which led to a significant decrease in the Bcl-2/Bax ratio. Immunoblotting demonstrated that ERK was briefly phosphorylated after seeding AML blasts into culture. PD98059, an inhibitor of MAPKinase kinase (MEK) which activates MAPKinase, inhibited this transient ERK phosphorylation but was unable to block maturation as measured by acquisition of CD15 in samples from 12 patients with low starting numbers of CD15-positive cells. PD98059, however, reduced cell numbers in 7-d liquid culture and, in cytokine-supplemented cultures, this was associated with a 1.3-fold increase in Bcl-2 (p = 0.012) and a 1.4-fold increase in Bax (p = 0.02). Overall, these data demonstrate that most leukemic populations can partially differentiate in vitro without the need for cytokines or inducers. The MAPKinase pathway is not required for this maturation, but it does maintain cell viability in the absence or presence of cytokines. A rise in Bcl-2 may not protect AML blasts in the face of elevated Bax.
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PMID:The MEK inhibitor, PD98059, reduces survival but does not block acute myeloid leukemia blast maturation in vitro. 1077 91

About 30%-40% of hematopoietic stem cells in human fetal liver of 3-5 months are in S phase of cell cycle, much higher than the ratio of 10% of that in adult bone marrow. The existance of highly active hematopoietic stem cell proliferation stimulators is probably its molecular basis. CFU-S "suicide rate" in rats was adopted to detect the effective substance. Through several steps of separation, we obtained a relatively purified substance of 35 kDa, termed it as FLS-4. CD 34 positive cord blood cells were sorted and assayed for their response to FLS-4 in 3H-TdR incorporation assay. The response to FLS-4 alone was approximately 1 times the background response seen with no factor added. In combination with IL-6 and IL-3 produced response that was 2.9 and 6.5 fold respectively greater than that observed with no factor added, but was weakly in comparison with the effects of SCF. In combination with GM-CSF or IL-3, FLS-4 can stimulate the formation of blast-colonies. The results indicate that the FLS-4 is very likely to be a novel hematopoietic stem cell proliferation stimulator. In physical or biological characteristics, it exhibited a unique character different from IL-3, IL-6, GM-CSF, SCF or FLT3 ligand those are known to have hematopoietic stem cell proliferation stimulating activity. During the period of active hematopoiesis in fetal liver, FLS-4 might be the candidate in triggering hematopoietic stem cells from resting G0 to S phase.
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PMID:[Studies of a 35 KDa substance from human fetal liver on the regulation of hematopoiesis]. 1103 18

We studied cytokine-driven differentiation of primitive human CD34(+)HLA-DR(-) cells to myeloid dendritic cells (DC). Hemopoietic cells were grown in long-term cultures in the presence of various combinations of early acting cytokines such as FLT3-ligand (FLT3-L) and stem cell factor (SCF) and the differentiating growth factors GM-CSF and TNF-alpha. Two weeks of incubation with GM-CSF and TNF-alpha generated fully functional DC. However, clonogenic assays demonstrated that CFU-DC did not survive beyond 1 wk in liquid culture regardless of whether FLT3-L and/or SCF were added. FLT3-L or SCF alone did not support DC maturation. However, the combination of the two early acting cytokines allowed a 100-fold expansion of CFU-DC for >1 month. Phenotypic analysis demonstrated the differentiation of CD34(+)DR(-) cells into CD34(-)CD33(+)DR(+)CD14(+) cells, which were intermediate progenitors capable of differentiating into functionally active DC upon further incubation with GM-CSF and TNF-alpha. As expected, GM-CSF and TNF-alpha generated DC from committed CD34(+)DR(+) cells. However, only SCF, with or without FLT3-L, induced the expansion of DC precursors for >4 wk, as documented by secondary clonogenic assays. This demonstrates that although GM-CSF and TNF-alpha do not require additional cytokines to generate DC from primitive human CD34(+)DR(-) progenitor cells, they do force terminal differentiation of DC precursors. Conversely, FLT3-L and SCF do not directly affect DC differentiation, but instead sustain the long-term expansion of CFU-DC, which can be induced to produce mature DC by GM-CSF and TNF-alpha.
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PMID:Stem cell factor and FLT3-ligand are strictly required to sustain the long-term expansion of primitive CD34+DR- dendritic cell precursors. 1114 59

CD14-positive monocytes obtained from human peripheral blood were cultured with GM-CSF and IL-4. During the early culture phase immature dendritic cells (DCs) developed which not only expressed CD1a, HLA-DR and CD86, but also expressed the endothelial cell markers von Willebrand factor (vWF), VE-cadherin and VEGF receptors Flt-1 and Flt-4. Further maturation of DCs was achieved by prolonged cultivation with TNFalpha. These cells showed typical DC morphology and like professional antigen-presenting cells (APCs) expressed CD83 and high levels of HLA-DR and CD86. However, if immature DCs were grown with VEGF, bFGF and IGF-1 on fibronectin/vitronectin-coated culture dishes, a marked change in morphology into caudated or oval cells occurred. In the presence of these angiogenic growth factors the cultured cells developed into endothelial-like cells (ELCs), characterized by increased expression of vWF, KDR and Flt-4 and a disappearance of CD1a and CD83. Addition of IL-4 and Oncostatin M also increased VE-cadherin expression, and the loosely adherent cells formed clusters, cobblestones and network-like structures. vWF- expressing ELCs mainly originated from CD1a-positive cells, and VEGF was responsible for the decrease in the expression of the DC markers CD1a and CD83. In mixed leukocyte cultures, mature DCs were more potent APCs than ELCs. Moreover, Ac-LDL uptake, and the formation of tubular structures on a plasma matrix was restricted to ELCs. These results suggest that in the presence of specific cytokines immature DCs have the potential to differentiate along different lineages, i.e. into a cell type resembling ELCs.
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PMID:Dendritic cells derived from peripheral monocytes express endothelial markers and in the presence of angiogenic growth factors differentiate into endothelial-like cells. 1121 40

In order to explore possible mechanisms involved in the previously documented turnover of mast cell subpopulations in human cutaneous scars, we have examined selected factors known to stimulate and/or modulate mast cell hyperplasia (SCF, NGF, TGFbeta1, GM-CSF) and their receptors in human cutaneous scar tissue. On immunohistochemistry, numbers of SCF- and TGFbeta1-positive cells were significantly increased in the epidermis and throughout the dermis in scars (n = 27) of varying ages (4-369 d old), compared with normal skin (n = 12). Furthermore, TRbetaRI, II, and the NGF-p75 receptors were significantly increased in the epidermis, TRbetaRI and NGF-TrkA throughout the dermis, and TRbetaRII, NGF-p75, and GM-CSFR only in the mid- and lower dermis of scars. NGF and GM-CSF expression was in contrast scarce and weak, with no differences between normal skin and scars. In tissue extracts, mRNA levels of SCF, TGFbeta1, TRbetaI and II, and both NGF-receptors, but not GM-CSFR, were significantly increased as well. TRbetaI and II were identified in up to 90% and 83%, respectively, of isolated normal skin mast cells on flow cytometry, and GM-CSFR and NGFR-p75 were identified on 70% and 73%, respectively, of avidin-positive normal mast cells on double immunofluorescence microscopy. As described before for the SCF receptor KIT, GM-CSFR and NGFR-p75 were partly or entirely downregulated on avidin-positive mast cells in scars. The marked upregulation of TGFbeta1, its type I and II receptors, and SCF suggest that these factors play a major role in the orchestration of mast cell increase in human cutaneous scars whereas the role of NGF and GM-CSF is less clear, despite the significant upregulation of their receptors.
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PMID:Expression of mast cell growth modulating and chemotactic factors and their receptors in human cutaneous scars. 1123 12

It has been proposed that adoptive immunotherapy, for the treatment of relapsed AML, with cytotoxic T lymphocytes which show a relative specificity for the leukemic cells may have the advantage of maximizing the beneficial anti-leukemic effect whilst minimizing the probability of graft-versus-host disease. In this study we differentiated peripheral blood AML cells in vitro into functional dendritic cells (DCs), as demonstrated by cell morphology, immunophenotype and functional activity, in the presence of GM-CSF, IL-4, TNF-alpha and FLT3 ligand. Such DCs could be differentiated from 77% of AML patients, irrespective of their FAB classification and clinical status and, in all cases tested, the DCs were shown to derive from the leukemic clone by FISH analysis. Importantly, from >60% of AML patients, autologous T lymphocytes stimulated with these in vitro generated leukemic DCs displayed specific cytotoxic activity against AML blasts but low reactivity against autologous non-leukemic targets and HLA-matched normal PBMNCs therefore suggesting that the CTLs were AML-specific. The use of FLT3 ligand in our system resulted in a significantly higher number of leukemic DCs as compared to cultures from which FLT3 ligand was omitted which is obviously advantageous if large numbers of specific CTLs are to be generated in the shortest possible time.
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PMID:Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia. 1123 40

Steel factor (SLF) plus GM-CSF induces proliferative synergy in factor-dependent cell line MO7e and hematopoietic progenitor cells. We previously reported ERK1/2 involvement in this synergy, but its downstream signaling molecules are not defined. Here, we investigated activation of the 90-kDa ribosomal S6 kinase (RSK) proteins by measuring the phosphorylation status and in vitro kinase activity in MO7e cells. Both GM-CSF and SLF induced activation of RSK, and the combined stimulation with these two cytokines induced synergistic and persistent activation of RSK. RSK activity was reduced by PI3 kinase inhibitor LY294002 or MEK1 inhibitor PD98059, suggesting that the ERK as well as the PI3 kinase pathways are involved in regulation of RSK activity. Sensitivities of RSK activity to inhibitory drugs correlated well with those of c-fos gene induction. Taken together, synergistic activation of RSK may contribute, at least in part, to the synergistic induction of c-fos after combined stimulation with GM-CSF plus SLF.
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PMID:Synergistic activation of RSK correlates with c-fos induction in MO7e cells stimulated with GM-CSF plus Steel factor. 1123 44

The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 microg m(-2)by intravenous infusion plus GM-CSF 5 microg kg(-1)day(-1)by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21-188) days. Toxicity was generally NCI-CTG 0-2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71-184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted.
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PMID:A phase II study of the bispecific antibody MDX-H210 (anti-HER2 x CD64) with GM-CSF in HER2+ advanced prostate cancer. 1146 Oct 69


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