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)

Macrophage stimulating protein (MSP) is a chemotactic factor for murine peritoneal macrophages. The receptor for human MSP was recently identified as the ron gene product, a transmembrane protein tyrosine kinase cloned from a human keratinocyte cDNA library. Here we report that MSP induced proliferation of murine primary keratinocytes and established keratinocyte cell lines in a concentration-dependent manner. The growth efficacy of MSP was comparable to that of epidermal growth factor and keratinocyte growth factor. In three of four cell lines tested in a chemotaxis chamber, MSP also stimulated migration of keratinocytes on a collagen type IV substratum. The action of MSP was mediated by specific binding of MSP to the STK gene product, a murine homologue of the RON MSP receptor. Binding of MSP to keratinocyte STK induced phosphorylation of the 150 kDa STK beta chain. Herbimycin A, a protein tyrosine kinase inhibitor, blocked MSP-mediated phosphorylation of the STK receptor as well as proliferation of keratinocytes, suggesting the importance of tyrosine kinase activity for transduction of the message delivered by MSP. Previously, the only known target cell for MSP was the resident peritoneal macrophage. These studies establish the keratinocyte as a new target cell for MSP. The action of MSP on keratinocytes may have implications for tissue repair, wound healing, and tumor growth.
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PMID:Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes. 866 Sep 37

Surgical resection has been the standard approach for primary and metastatic liver tumors. Long-term survival, however, is limited because of recurrence or hepatic decompensation. Failure of chemotherapeutic regimens or liver transplantation (OLT) to prevent recurrence has resulted in the need for multimodality therapies. We report our experience with preoperative hepatic arterial chemoembolization (CET) followed by OLT in highly select patients. Over a 33-month period, 23 of 41 patients (56%) referred with primary (n = 16) or metastatic neuroendocrine (n = 7) liver tumors met eligibility requirements. Despite mild, self-limited chemical hepatitis, CET was well tolerated in all but three elderly patients who succumbed to liver failure. Four of five patients ultimately received OLT. Three are alive and free of disease at a mean followup of 17 months, one died of recurrent hepatocellular carcinoma, and one (NET) remains well at 33 months with elevated glucagon levels but no measurable disease. All NET patients are alive with resolution of hormonal symptoms. Four of five noncirrhotic patients died of disease, and one has progressive tumor growth. Although OLT following CET achieves superior survival, its application is limited to a minority of patients with such tumors. Careful pretreatment staging and patient selection combined with caution in the use of CET in elderly cirrhotic patients is critical to the success of such therapies.
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PMID:Intrahepatic arterial chemoembolization for hepatocellular carcinoma and metastatic neuroendocrine tumors in the era of liver transplantation. 875 63

Neoangiogenesis is a prerequisite for tumor growth and metastasis. In germ cell cancer patients with the disease limited to the testicle (stage A), tumor-associated neovascularization is predictive of metastatic disease (stage B). To investigate the molecular mechanisms underlying neovascularization in human germ cell tumors (GCTs), we analysed the expression of two angiogenic growth factors, vascular endothelial growth factor (VEGF) and placenta growth factor (P1GF), and of their receptors (FLT-1) and Flk-1/KDR) in a panel of testicular tumors. In this study we show a marked increase in VEGF expression in 36/44 (81.8%) primary testicular-derived GCTs, as compared to normal testis, that significantly correlates with a high density of intratumor microvessels (r = 0.72461, P < 0.001; n = 24). As determined by RT - PCR and/or Western blot, the predominant VEGF isoforms expressed in GCTs are the VEGF121 and VEGF165, which are more efficiently secreted by the cells, and thus more active in eliciting angiogenesis. Conversely, in the case of PIGF, only a weak correlation with the vascular density of tumors is observed (r = 0.26599, P < 0.05; n = 24). Northern blot analysis also revealed significant up-regulation of VEGF/ PIGF receptors in highly vascularized germ cell tumors, compared to normal testes. These findings suggest that VEGF may act in a paracrine manner to induce neovascularization, oedema extravasation and cyst formation in human germ cell tumors. The correlation between VEGF expression and the vascular density of tumors, suggest that the evaluation of VEGF expression may be of help in predicting patients at risk for metastatic diseases. Finally, we demonstrate that VEGF up-regulation may occur at the RNA level since no gene amplification is observed; conversely, in in vitro models such as the embryonal stem cell line NTERA-2 and the choricarcinoma JEG-3 cell line, VEGF (but not PIGF) mRNA expression is regulated by hypoxic stress.
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PMID:Neovascularization in human germ cell tumors correlates with a marked increase in the expression of the vascular endothelial growth factor but not the placenta-derived growth factor. 876 Feb 99

Many tumors exhibit loss of heterozygosity (LOH) for polymorphic markers in regions of the genome that contain genes whose normal function can suppress tumor growth. Mapping of regions of LOH can help identify putative tumor suppressor loci that play a role in the pathogenesis of a disease. We evaluated 18 chondrosarcomas for LOH at 17 short tandem-repeat polymorphism loci on chromosome 10. Sixty-seven percent of the tumors (12/18) showed LOH for at least one marker and in most of these tumors the region of loss spanned all or large portions of the chromosome. By determining the smallest segment consistently involved, we identified a 7-12 cM critical region for LOH in the proximal long arm. This genomic region contains the RET oncogene, which has been implicated in the pathogenesis of multiple endocrine neoplasia types 2A and 2B, Hirschsprung disease, and medullary and papillary thyroid carcinomas. LOH on chromosome arm 10q was found in early-stage chondrosarcomas and did not correlate with grade or prognosis. Inactivation or alteration of a gene located at this site may be an early event in the development of these tumors.
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PMID:Frequent loss of heterozygosity for markers on chromosome arm 10q in chondrosarcomas. 881 61

Expression of the tyrosine-kinase receptor encoded by the c-KIT proto-oncogene progressively decreases during local tumor growth and invasion of human melanomas. To provide direct evidence that c-KIT plays a role in metastasis of human melanoma, we transfected the c-KIT gene into the c-KIT negative highly metastatic human melanoma cell line A375SM and subsequently analysed its tumorigenic and metastatic potential. A375SM parental cells, A375SM-NOT (neo, control), and A375SM-KIT-positive cells were injected s.c. and i.v. into nude mice. A375SM-KIT cells produced significantly slower growing s.c. tumors and fewer lung metastases than control cells. Exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of c-KIT-negative melanoma cells or normal melanocytes. Since SCF is produced by keratinocytes and other dermal cells in the skin, these results suggest that the loss of c-KIT receptor expression may allow malignant melanoma cells to escape SCF/c-KIT-mediated apoptosis, hence contributing to tumor growth and eventually metastasis. The antitumor and antimetastatic properties of SCF may be useful in treating human melanomas in early stages.
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PMID:Enforced c-KIT expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential. 895 75

Integrins can trigger signals by activation of cytoplasmic tyrosine kinases, including pp125FAK. Preliminary evidence suggests that serine/threonine kinases such as ERKs may also be activated via integrins. Thus, there seems to be at least partial overlap between RTK signaling pathways and integrin signaling. In tumor cells, ectopic expression or over-expression of certain integrins such as alpha 5/beta 1 can result in reduced tumorigenesis. Presumably the effects of integrins on tumor growth are mediated by the integrin signaling pathway(s) involving FAK and ERKs. However, the precise mechanisms involved have not yet been elucidated.
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PMID:Integrin signals and tumor growth control. 898 69

Hypopharyngeal squamous cell carcinomas (HPC) has an extremely poor prognosis. Characteristics of cell lines of head and neck squamous cell carcinomas including HPC were studied by various methods, e.g., chemosensitivity test and the immunohistochemistry staining method, to determine whether this poor prognosis is due to the biological behavior of this cancer. An HPC cell line was found to be resistant to anti tumor drugs, i.e., PEP, MTX and CPM and moderately sensitive to CDDP, 5-FU and ADM. Thermoresistance to hyperthermatic treatment and weak expression of ICAM-1 on the HPC cell line were observed. DNA synthesis by the HPC cell line was induced by stimulation with a low concentration of EGF and the amount of EGFR on these HPC cells was very high. In addition, cyclinD1 overexpression was found in the HPC cell line. Based on the above findings, further analysis of hypopharyngeal carcinoma cells and the development of a new treatment modality to control tumor growth and metastatic factors influencing the poor outcome are necessary to improve the prognosis of this cancer.
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PMID:[Biological behavior of hypopharyngeal carcinoma]. 903 77

The comparative biological properties of NBT-II cells, a rat bladder carcinoma cell line constitutively expressing FGF-1 and FGF-2 were analysed in nude mice. FGF-1 is not secreted by the transfected cells unless the cDNA contains a signal sequence; conversely, NBT-II cells transfected with FGF-2 coding sequence produce and secrete the factor in a biologically active form. Bovine brain capillary endothelial cells are stimulated to proliferate upon addition of medium conditioned by the FGF-2-producing cells and this activity can be abrogated by the addition of anti-FGF-2 blocking antibodies. In addition, the FGF-2-containing medium, which cannot stimulate NBT-II cells due to absence of appropriate receptors, is able to induce scattering of NBT-II cells expressing the FGFR1. It has been reported previously that FGF-1-producing cells are highly tumorigenic in nude mice and induce carcinoma with a period of latency reduced from 6 to 5 weeks when compared to parental NBT-II cells. In contrast, NBT-II cells producing FGF-2 are no more tumorigenic than parental cells, indicating that FGF-1 and FGF-2 have different oncogenic properties in carcinoma. FGF-1 and FGF-2 are potent antiogenic factors that trigger the host endothelial cells. VEGF, another potent angiogen was found to be expressed in small amounts by NBT-II cells and to be expressed in reduced amount in the FGF-producing cells. In the NBT-II system in vivo FGF-1 and FGF-2 are highly and comparatively angiogenic in the resultant carcinoma and this occurs in the absence of production of significant amounts of VEGF by the carcinoma cells. Taken together, our results indicate that activated angiogenesis is not sufficient for rapid tumor expansion. FGF-1 behaves as a tumorigenic factor in the NBT-II bladder carcinoma cell model, whereas expression and secretion of large amounts of FGF-2 are not sufficient for increasing tumor growth.
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PMID:FGF-2 and FGF-1 expressed in rat bladder carcinoma cells have similar angiogenic potential but different tumorigenic properties in vivo. 903 74

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is an angiogenic factor with important roles in tumor growth, wound healing, and inflammation. VPF/VEGF interacts with endothelial cells by way of two high-affinity receptor tyrosine kinases: flt-1 and KDR. The vast majority of published studies have described expression of the VPF/VEGF receptors only in endothelial cells, and the statement is frequently made that these receptors are endothelial-cell-specific. In this study, we detected mRNA for flt-1 and KDR by in situ hybridization in smooth muscle cells in sections of the wall of the uterus. To confirm these unexpected findings, smooth muscle cells from the uterus and, as a control, from the colon were isolated, characterized, and cultured. Both uterine and colonic smooth muscle cells in culture expressed VPF/VEGF, but only smooth muscle cells from the uterus expressed mRNA for flt-1 and KDR by Northern analysis and in situ hybridization. Cell culture extracts of uterine but not colonic smooth muscle cells were also positive for flt-1 by Western analysis. Moreover, cultured uterine but not clonic smooth muscle cells phosphorylated the flt-1 receptor and proliferated strongly in response to added VPF/VEGF. This is one of the first rigorous demonstrations that a normal cell type other than endothelial cells can express functional receptors for VPF/VEGF in vivo and in vitro, suggesting that VPF/VEGF may have important, previously unsuspected roles on cell types other than endothelium.
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PMID:Uterine smooth muscle cells express functional receptors (flt-1 and KDR) for vascular permeability factor/vascular endothelial growth factor. 904 61

Bone marrow (BM) stromal cells are required for normal hematopoiesis. A number of soluble factors secreted by these cells that mediate hematopoiesis have been characterized. However, the mechanism of hematopoiesis cannot be explained solely by these known factors, and the existence of other, still unknown stromal factors has been postulated. We showed that hepatocyte growth factor (HGF) is one such cytokine produced by human BM stromal cells. BM stromal cells were shown to constitutively produce HGF and also to express the c-MET/HGF receptor. The production of HGF was enhanced by addition of heparin and phorbol ester. Dexamethasone and tumor growth factor-beta (TGF-beta) inhibited the production of HGF. Interleukin-1 alpha (IL-1 alpha) tumor necrosis factor-alpha (TNF-alpha), and N6,2'-o-dibutyryl-adenosine-3':5'-cyclic monophosphate (dbc-AMP) showed no obvious influence on HGF production. Western blot analysis of HGF derived from BM stromal cells showed two bands at 85 and 28 kD corresponding to native and variant HGF, respectively. Addition of recombinant HGF significantly promoted the formation of burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte erythroid macrophage (CFU-GEM) by BM mononuclear cells in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF), but the formation of CFU-GM was not modified. However, HGF had no effects on colony formation by purified CD34+ cells. Within BM mononuclear cells, c-MET was expressed on a proportion of cells (CD34-, CD33+, CD13+, CD14+, and CD15+), but was not found on CD34+ cells. We conclude that HGF is constitutively produced by BM stromal cells and that it enhances hematopoiesis. In addition, expression of c-MET on the stromal cells suggests the presence of an autocrine mechanism, operating through HGF, among stromal cells.
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PMID:Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and indirectly promotes hematopoiesis. 905 37


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