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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This laboratory has evaluated the subrenal capsular assay system previously in the Nb rat with the Nb rat prostate adenocarcinoma model. Human renal cell carcinoma xenografts are now being employed in our Nb rat SRC model, the advantage of this system being that one can determine the effect of chemotherapy in a very short period of time, i.e., 7 days. This method saves considerable time and expense and may serve as a useful indicator for effective chemotherapeutic agents in individual cancer patients. In our studies, cyclophosphamide was the only agent to produce a significant effect on tumor volume.
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PMID:First--generation human renal cell carcinoma xenografts in the Nb rat subrenal capsular assay model. 297 66

A new embolic material has been devised to improve the therapeutic effect of ferromagnetic embolization upon tumors. Iron sponge microspheres (diameter 10-30 mu) were suspended in viscous, aqueous polysaccharide solution, dextran 40, and sodium carboxymethyl cellulose (Ferro-polysaccharide, FPS). Transcatheter embolization with FPS was performed under external magnetic control (2,800 gauss) in dog kidneys and VX2 carcinomas of rabbits, causing widespread, intraparenchymal vascular occlusion of target vessels. Neither recanalization nor collateral circulation was found to the infarcted areas, and the embolized tumors had extensive necrosis with resultant tumor regression. No significant untoward reaction or other undesirable embolization was noted serologically or histologically, even after intravenous administration of FPS. Clinical application to two patients, one with a hepatoma and the other with a renal cell carcinoma, resulted in excellent tumor infarction with no significant side effects.
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PMID:Transcatheter microembolization with ferropolysaccharide. A new approach to ferromagnetic embolization of tumors: preliminary report. 618 53

To identify protein tyrosine kinase (PTK) genes preferentially expressed in renal cell carcinoma cell line, we screened a PTK-cDNA-enriched library constructed from RNA of an renal cell carcinoma cell line with a PTK probe, each produced from renal cell carcinoma, gastric cancer or esophageal cancer cell lines by degenerate polymerase chain reaction. Two cDNA fragments of PTK genes, FRK and FLT-3, were isolated from the PTK-cDNA-enriched library of the renal cell carcinoma cell line by differential hybridization technique. The FRK cDNA clone represented 15.8% of the PTK-cDNA-enriched library from the renal cell carcinoma cell line, while the FLT-3 cDNA clone was 2.8% of the same library. Both of the two PTK genes were expressed preferentially in renal cell carcinoma cell lines. This method, described here, is useful for the rapid isolation of PTK cDNA fragments, including a low abundant cDNA, preferentially expressed in a specific cell line.
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PMID:Rapid isolation of cell-type-specific protein tyrosine kinases by degenerate polymerase chain reaction combined with differential hybridization technique. 766 53

An orthotopic metastatic human renal cell carcinoma model in nude mice was established to evaluate the mechanism of metastasis as a preliminary phase in the development of a treatment to prevent cancer metastasis. The effect of host fibroblasts from different organs on the production of type IV collagenase by human renal cell carcinoma and the factors which influenced the enzyme production and secretion by fibroblasts were also investigated. KG-2 cells were established from human renal cell carcinoma, and produced tumors following implantation to both the subrenal capsular space (orthotopic site) and subcutis (ectopic site). Histologically, the tumors in the subcuit (SC tumors) were well encapsulated with a thick fibrous capsule and did not produce metastasis or invasion, whereas those in the subrenal capsular space (SRC tumors) lacked a fibrous capsule and produced metastasis at the lung or regional lymph nodes. The production of type IV collagenase in conditioned media from metastatic SRC tumors and lung metastatic lesions was larger than that from non-metastatic SC tumors. The conditioned media separated from mouse kidney or lung fibroblasts stimulated the production of type IV collagenase by KG-2 cells, whereas, that separated from mouse skin fibroblasts decreased the enzyme production. The production of type IV collagenase by KG-2 cells was stimulated by cocultured KG-2 cells and fibroblasts from the kidney or lung, whereas it was suppressed by cocultured KG-2 cells and skin fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Role of organ specific fibroblasts in metastasis of human renal cell carcinoma: regulation of type IV collagenase production from human renal cell carcinoma by organ specific fibroblasts]. 799 8

Integrins from normal human renal cortex epithelial cells (RCEC) and from four renal carcinoma lines (metastatic Caki-1, non-metastatic Caki-2, metastatic ACHN, and non-metastatic 769-P) were compared by immunoprecipitation with specific anti-integrin antibodies. Integrin alpha 2 was present in normal RCEC, but absent in all four tumor lines. There was a 2.0-3.0 fold decrease of alpha 3 and beta 1 in localized tumor lines, and a further 5.0-7.0 fold decrease in metastatic lines over their expression in normal renal cells. No alpha V was detected in Caki-1 cells. The greatest adhesion of all cells occurred in the presence of a stimulatory anti-alpha 3 antibody, mediated by specific matrix proteins employed as substrates, while anti-beta 1 treatment dramatically inhibited cell attachment on collagen IV, plasma fibronectin, laminin and merosin substrates. In addition, the mRNA expression of focal adhesion kinase (p125FAK) and paxillin were up-regulated (2.0-2.5 fold increase) in the metastatic Caki-1 cells over normal RCEC. The alteration of integrin subunits alpha 2, alpha 3, alpha V, beta 1, as well as p125FAK and paxillin may contribute to the pathogenicity and/or metastatic propensity of renal epithelial tumors. The up-regulation of paxillin independently or in concert with p125FAK as shown in this study indicates its significant role as a potential marker of metastasis in renal carcinoma cells.
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PMID:Integrin expression on cell adhesion function and up-regulation of P125FAK and paxillin in metastatic renal carcinoma cells. 902 46

The proliferative capacity of T cells infiltrating human tumors is known to be impaired, possibly through their interaction with tumor. Here we demonstrate that soluble products derived from renal cell carcinoma (RCC-S) explants but not normal kidney can inhibit an IL-2-dependent signaling pathway that is critical to T cell proliferation. A major target of the immunosuppression was the IL-2R-associated protein tyrosine kinase, Janus kinase 3 (Jak3). RCC-S suppressed basal expression of Jak3 and its increase following stimulation with anti-CD3/IL-2. Jak3 was most sensitive to suppression by RCC-S; however, reduction in expression of p56(lck), p59(fyn), and ZAP-70 was observed in some experiments. Expression of other signaling elements linked to the IL-2R (Jak1) and the TCR (TCR-zeta, CD3-epsilon, and phospholipase C-gamma) were minimally affected. In naive T cells, RCC-S also partially blocked induction of IL-2R alpha-, beta- and gamma-chain expression when stimulating via the TCR/CD3 complex with anti-CD3 Ab. To determine whether RCC-S suppressed IL-2-dependent signaling, primed T cells were employed since RCC-S had no effect on IL-2R expression but did down-regulate Jak3 expression and, to a lesser degree, p56(lck) and p59(fyn). Reduction in Jak3 correlated with impaired IL-2-dependent proliferation and signal transduction. This included loss of Jak1 kinase tyrosine phosphorylation and no induction of the proto-oncogene, c-Myc. These findings suggest that soluble products from tumors may suppress T cell proliferation through a mechanism that involves down-regulation of Jak3 expression and inhibition of IL-2-dependent signaling pathways.
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PMID:Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling: role of soluble products from human renal cell carcinomas. 930 Jul 31

To screen the receptor genes in renal cell carcinoma (RCC) associated with angiogenesis, we performed differential hybridization of the cDNA library of membrane-type protein tyrosine kinases (mPTKs). Three thousand plaques of a mPTKs-enriched cDNA library were screened with mPTKs mixture probes produced from hypervascular RCC tissues and RCC cell lines. Six different cDNA fragments of the PTK genes were isolated, and the sequence analysis showed that these represented cDNAs for TIE1, KDR, FMS, FGFR-4, JAK1 and HCK. Of these genes, the expression of TIE1, KDR, and FGFR-4 was studied in RCC tissue and cell lines by Northern blot analysis. We also investigated the expression of vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and their receptor FLT-1. In all the hypervascular RCC tissues, the amounts of mRNAs for KDR and FLT-1 were increased compared to adjacent normal tissues. The TIE1 and FGFR-4 genes were also overexpressed in most of the hypervascular RCC tissues, while no mRNA of KDR, FLT-1, or TIE1 could be detected in any of the four human RCC cell lines. The amounts of the VEGF and PlGF mRNAs were increased in hypervascular RCC tissues, while VEGF mRNA was detected in the four cell lines but PlGF mRNA was not. FGFR-4 mRNA was expressed in three of the four cell lines. These results suggest that KDR, FLT-1, PlGF and TIE1 mRNAs are present in the mesenchymal cells of RCC, while VEGF and FGFR-4 genes are expressed in RCC cells themselves in vivo.
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PMID:Identification of receptor genes in renal cell carcinoma associated with angiogenesis by differential hybridization technique. 1020 73

Disialylgalactosylgloboside (DSGG), defined by monoclonal antibody RM2, is a renal cell carcinoma (RCC)-associated antigen which mediates adhesion of RCC TOS-1 cells to certain lung tissue target cells. This adhesion process may initiate preferential lung metastasis of RCC. Ganglioside GM3 is a B16 melanoma-associated antigen which similarly adheres to target cells and promotes consequent metastasis. In view of the close association of GM3-enriched microdomain with transducer molecules c-Src, Rho A, and FAK in B16 cells, we investigated the organizational status of DSGG in RCC cell line TOS-1, with the following results: i) DSGG, but not monosialylgalactosylgloboside, showed extensive clustering at the TOS-1 cell surface; ii) a low-density membrane fraction isolated from TOS-1 cells contained >95% of cellular DSGG, although protein content in this fraction was <1% of total cellular protein; iii) this fraction contained c-Src, Rho A, and FAK, but not H-Ras; iv) c-Src and Rho A were co-immunoprecipitated with DSGG through anti-DSGG mAb RM2 (IgM) affixed to a column. These observations indicate that DSGG is clustered in RCC, as typified by TOS-1 cells, to form a microdomain in which it is closely associated with c-Src, Rho A, and FAK, and may constitute a functional unit as has been observed for GM3 with transducer molecules in B16 cells. The functional organization of such units may be essential in determining malignant properties of RCC cells.
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PMID:Association of renal cell carcinoma antigen, disialylgalactosylgloboside, with c-Src and Rho A in clustered domains at the surface membrane. 1067 85

We recently described germline and somatic mutations in the MET gene associated with papillary renal carcinoma type 1. MET mutation M1268T was located in a codon highly conserved among receptor tyrosine kinases, and homologous to the codon mutated in multiple endocrine neoplasia type 2B, and many cases of sporadic medullary carcinoma of the thyroid gland (Ret M918T). Ret M918T and MET M1268T have previously been shown to be highly active in mouse NIH3T3 transformation assays, and to change the substrate specificity of the kinase. We studied the mechanism of transformation mediated by MET M1268T by analysing a clone, F4, derived from NIH3T3 cells transformed by MET M1268T. In contrast to NIH3T3 cells, F4 cells grew in suspension in tissue culture, and rapidly formed tumors in nude mice. We found that c-Src was constitutively bound to MET proteins in F4 cells, and that Src kinase activity was elevated. Transfection of dominant negative Src constructs into F4 cells eliminated the ability of F4 cells to grow in suspension culture and retarded the growth of F4 cells in vivo. The ability of transfected dominant negative Src constructs to inhibit the growth of F4 cells correlated with the inhibition of phosphorylation of paxillin and focal adhesion kinase. Transfection of dominant negative Src constructs into F4 cells had no effect on Grb2 binding or PLC gamma phosphorylation. The results suggest that c-Src participates in the tumorigenic phenotype induced in NIH3T3 cells by MET M1268T by signaling through focal adhesion kinase and paxillin. Oncogene (2000).
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PMID:Tumorigenesis mediated by MET mutant M1268T is inhibited by dominant-negative Src. 1087 51

The granulin-epithelin precursor, progranulin, PC-cell-derived growth factor or acrogranin, is a high molecular weight secreted mitogen. It is abundantly expressed in rapidly cycling epithelial cells, in the immune system and in neurons, such as cerebellar Purkinje cells. Progranulin contributes to tumorigenesis in diverse cancers, including breast cancer, clear cell renal carcinoma, invasive ovarian carcinoma and glioblastoma. It regulates the rate of epithelial cell division in responsive epithelial cells, and confers an invasive phenotype on these cells. It is involved in the wound response. During embryogenesis, progranulin accelerates blastocyst formation, and is a growth factor for trophectodermal cells. In the neonate, progranulin, regulates the hormone-dependent virilization of the hypothalamus. It activates phosphorylation of Shc, and p44/42 MAPK (mitogen activated protein kinase) in the ERK (extracellular regulated kinase) signaling pathway; PI3K (phosophatidyl inositol-3-kinase), AKT/protein kinase B, and p70S6kinase in the phosophatidyl inositol-3-kinase pathway; and focal adhesion kinase in the adhesion/motility pathway. The signaling properties of progranulin are apparently similar to those of classic growth factors, but the functional properties of progranulin distinguish it from these molecules. Deleting the insulin-like growth factor I receptor from murine embryonic fibroblasts blocks proliferation in response to all classic growth factors, such as epidermal growth factor, or platelet-derived growth factor, whereas progranulin retains mitotic activity on these cells. The defined biological actions of progranulin probably represent a small fraction of its overall functions. Transcriptome analyses show that the progranulin gene is induced in numerous situations that vary from obesity to the transcriptional response of cells to antineoplastic drugs. Here, the biological roles of progranulin will be reviewed, with an emphasis on cancer and cell proliferation.
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PMID:Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. 1297 94


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