Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cryostat sections of normal skin from 57 white adults were examined by direct and indirect immunofluorescence for immunoglobulins, complement factors, and transferrin. The results for basement membrane zone (BMX) were significantly different for the 11 face and 46 non-face biopsies: in the face, IgM was found in five, IgG in two, IgA in one, and C3 in none, whereas, in non-face, IgM was present in six, IgG in none, IgA in one, and C3 in five. The results for dermal vessel walls (DV) were not apparently different for face and non-face; in the 57 biopsies IgM was present in one, IgG in none, IgA in one, and C3 in one. The 11 biopsies from the face and 26 of the non-face biopsies were examined further. No IgD or C4 was identified, but one case (scalp) showed BMZ Clq, properdin, and transferrin, and in two cases (one face, one non-face) DV properdin was found. Cytoid bodies (IgM and IgA) were present in moderate numbers in one case; all other positive reactions were finely granular.
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PMID:Immunoglobulin and complement in normal skin. 37 44

We have studied the in vitro uptake of gallium-67 by exponentially growing EMT-6 sarcoma cells in long-term tissue culture. In this system, the addition of transferrin to the medium was required before an appreciable cellular uptake of Ga-67 occurred. The transferrin effect was complex, with an initial stimulation to a peak cell-to-medium ratio of 8--10:1 at low concentrations of transferrin (0.2 mg/ml), followed by a gradual decline in uptake as transferrin in the medium was increased further. EMT-6 tumor-cell uptake of Ga-67 was probably mediated by a specific cellular receptor for transferrin. Scatchard analysis of the EMT-6 cellular binding of human transferrin labeled with iodine-125 indicated a cellular receptor with affinity for transferrin of 5 X 10(6) l/mole and abundance of 500,000 receptors per cell. Over the experimental range of transferrin concentration in the medium, the observed uptake of Ga-67 was closely correlated with the degree of formation of Ga-67-labeled transferrin and the fraction of transferrin bound to the cellular receptor (N = 69, r = 0.86, p less than 0.0001).
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PMID:A transferrin-mediated uptake of gallium-67 by EMT-6 sarcoma. I. Studies in tissue culture. 54 30

Aluminum (Al) overload in dialysis patients and experimental animals is associated with the development of anemia. However, the precise mechanisms of erythrocyte Al uptake and toxicity are poorly understood. Al accumulation, hemoglobin (Hb) synthesis and cell growth were evaluated in dimethylsulfoxide (DMSO)-induced Friend erythroleukemia cells (FEC), a model system for erythroid differentiation. FEC were grown in media containing either Al citrate, transferrin-aluminum (Tf-Al), Tf or no additions. Al accumulation occurring only in cells grown in Tf-Al containing media was detected at 24 hours and increased linearly up to 96 hours after induction. By 96 hours, 200 +/- 36 micrograms Al/liter lysed cells were detected in Tf-Al grown cells versus 5 +/- 1 micrograms Al/liter lysed cells in cells grown in Al citrate (P less than 0.001). Tf-Al inhibited Hb synthesis at 72 hours after induction. At 96 hours 50 +/- 15% cells were benzidine positive when grown in Tf-Al compared to 76 +/- 15% in Al citrate (P less than 0.001). FEC grown in increasing concentrations of Tf-Al (100 to 500 micrograms/ml) showed inhibition of Hb synthesis at lower concentrations of Tf-Al at 100 micrograms/ml than for cell growth at 300 micrograms/ml. Higher concentrations of Tf-Al (greater than 300 micrograms/ml) did not further inhibit Hb synthesis or cell growth. Iron (Fe) and Tf uptake were increased in Al loaded FEC compared to control cells. The increased Tf uptake was probably the result of increased Tf receptor expression on FES since Tf cell cycling time was unchanged. These data indicate that Al utilizes the Tf uptake pathway for entry into erythrocyte precursors. Al is toxic at sites distal to Fe uptake, possibly at the heme and/or globin synthetic pathways, resulting in decreased Hb synthesis and cell growth.
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PMID:Aluminum inhibits hemoglobin synthesis but enhances iron uptake in Friend erythroleukemia cells. 230 57

The effect of Amphotericin B (AMB) on radiogallium biodistribution in mice was studied at various time intervals. Two doses of AMB (1 mg/kg and 10 mg/kg) were administered intraperitoneally into mice bearing EMT-6 mammary sarcomas. The tumor and tissue uptakes of 67Ga were calculated when the radioactivity was administered either as 67Ga-citrate or 67Ga-transferrin (Ga-Tf). The role of transferrin was also investigated by using doubly-labeled 67Ga-125I-Tf. Our results indicate that both the doses of AMB and the chemical form of the radiogallium administered affect the pattern of distribution in some distinct fashion. It was also found that although the administration of AMB results in an increase in tumor-associated transferrin, this does not necessarily result in a concomitant increase in radiogallium uptake. In general, the effects of AMB on various tissues uptake of 67Ga appear to be related to both acute and subacute toxicity.
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PMID:The effect of amphotericin B on 67Ga biodistribution. 385 76

We studied the tumor uptake of [67Ga]citrate, [59Fe]citrate, and 125I-labeled transferrin (TF) by the in vitro growth form of EMT-6, a sarcoma-like mammary tumor of BALB/c mice. In analyzing the binding experiments, we developed a new mathematical model based on a formulation originally used to express the interaction of hormones with specific tissue receptors. The uptake of both carrier-free 67Ga and 59Fe by tumor cells was mediated by kinetically identical TF receptors. We also studied teric acid extracts of the stroma of EMT-6 tumors grown both in vivo and in vitro. Chromatography of these extracts on Sephacryl S-200 SF demonstrated that the cellular stroma contained specific TF-binding macromolecules. On the basis of these findings, we proposed the "transferrin receptor hypothesis" for the mechanism of 67Ga uptake by tumors. According to this view, a tumor-associated TF receptor is the functional unit responsible for the affinity of gallium for certain neoplasms. This receptor was also active in the uptake of iron by tumors.
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PMID:Common pathway for tumor cell uptake of gallium-67 and iron-59 via a transferrin receptor. 624 76

The cytotoxicity of citrated gallium nitrate (NSC 15200) to EMT-6/UW mouse sarcoma cells growing in vitro was assayed as growth inhibition in treated cultures as well as cell survival (colony-forming ability) after acute or chronic exposure to graded doses. Gallium nitrate is both cytostatic and lethal to cells, with some growth inhibition occurring after chronic exposure to low doses (10 micrograms/ml) which kill essentially no cells. Cell kill and growth inhibition were both observed if cells were exposed for 24 hr or more to doses greater than 50 micrograms/ml. The growth inhibitory and lethal effects of gallium nitrate were enhanced by the addition of human transferrin to the medium. This enhanced toxicity was consistent with, and proportional to, the increased gallium uptake in the presence of transferrin rather than a direct effect of this iron transport protein. The addition of ferric citrate greatly reduced the toxic effect of the gallium salt. Cells in stationary plateau phase cultures appear to be as sensitive to gallium nitrate as exponentially growing cells. Ga3+ may mimic Fe3+ in some aspects of cellular metabolism, and competition between the two metals occurs at the initial uptake step, binding to transferrin, and possibly at other points in cell metabolism.
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PMID:Tumor cell toxicity of stable gallium nitrate: enhancement by transferrin and protection by iron. 688 67

The aim of this work was to show in serum-free medium a convergent effect of physiological factors and extracellular matrix proteins on the differentiation process of enterocytes by taking as a model the HT29-D4 clone that has the feature of differentiating when subcultured in fetal bovine serum glucose-free medium. We show that triiodothyronine (T3) as well as insulin promotes limited cell growth and differentiation, whereas fibronectin or bovine serum albumin (BSA) induces cell growth and a low level of differentiation. However, insulin, T3, fibronectin, and BSA together with epidermal growth factor and transferrin promoted satisfactory growth and enterocyte morphology with epithelial electrophysiological properties in HT29-D4 cells. With these factors adequate protein targeting was achieved since cells apically expressed the carcinoembryonic antigen, and basolaterally transferrin and insulin receptors, beta 1 and alpha v beta 6 integrins, talin, vinculin, and focal adhesion kinase (FAK). Talin, vinculin, FAK, and alpha v beta 6 integrin, the fibronectin receptor, were clustered in focal contacts, which agrees with a possible role of fibronectin in final cell growth, the latter process mediating the final phase of differentiation. This level of differentiation can be maintained for a long time. Thus HT29-D4 cells appear to be a suitable model to study the implication of integrins in the differentiation process of human enterocytes.
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PMID:Convergent effects of growth factors, hormones, and fibronectin are necessary for the enterocyte differentiation of a colon adenocarcinoma cell line (HT29-D4). 981 Jul 9

An interaction of SNAP-23 and syntaxin 4 on the plasma membrane with vesicle-associated synaptobrevin-2 and/or cellubrevin, known as SNAP (soluble N-ethyl-maleimide-sensitive factor attachment protein) receptors or SNAREs, has been proposed to provide the targeting and/or fusion apparatus for insulin-stimulated translocation of the GLUT4 isoform of glucose transporter to the plasma membrane. By microinjecting 3T3-L1 adipocytes with the Clostridium botulinum toxin B or E, which proteolyzed synaptobrevin-2/cellubrevin and SNAP-23, respectively, we investigated the role of these SNAREs in GLUT4, GLUT1, and transferrin receptor trafficking. As expected, insulin stimulated the translocation of GLUT4, GLUT1, and transferrin receptors to the plasma membrane. By contrast, a constitutively active protein kinase B (PKB-DD) only stimulated a translocation of GLUT4 and not GLUT1 or the transferrin receptor. The GLUT4 response to PKB-DD was abolished by toxins B or E, whereas the insulin-evoked translocation of GLUT4 was inhibited by approximately 65%. These toxins had no significant effect on insulin-stimulated transferrin receptor appearance at the cell surface. Thus, insulin appears to induce GLUT4 translocation via two distinct routes, only one of which involves SNAP-23 and synaptobrevin-2/cellubrevin, and can be mobilized by PKB-DD. The PKB-, SNAP-23-, and synaptobrevin-2/cellubrevin-independent GLUT4 translocation pathway may involve movement through recycling endosomes, together with GLUT1 and transferrin receptors.
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PMID:Protein kinase B stimulates the translocation of GLUT4 but not GLUT1 or transferrin receptors in 3T3-L1 adipocytes by a pathway involving SNAP-23, synaptobrevin-2, and/or cellubrevin. 1049 59

One target for the small GTPase Cdc42 is the nonreceptor tyrosine kinase activated Cdc42-associated kinase (ACK), which binds selectively to Cdc42.GTP. We report that ACK1 can associate directly with the heavy chain of clathrin. A central region in ACK1 containing a conserved motif behaves as a clathrin adaptor and competes with beta-arrestin for a common binding site on the clathrin N-terminal head domain. Overexpressed ACK1 perturbs clathrin distribution, an activity dependent on the presence of C-terminal "adaptor" sequences that are also present in the related nonkinase gene 33. ACK1 interacts with the adaptor Nck via SH3 interactions but does not form a trimeric complex with p21-activated serine/threonine kinase, which also binds Nck. Stable low level expression of green fluorescent protein-ACK1 in NIH 3T3 cells has been used to localize ACK1 to clathrin-containing vesicles. The co-localization of ACK1 in vivo with clathrin and AP-2 indicates that it participates in trafficking, underlying an ability to increase receptor-mediated transferrin uptake.
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PMID:The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors. 1127 36

Increasing evidence suggests that altered gene expression is associated with the induction and maintenance of malignancy in various organs including mouse lung adenocarcinomas. A competitive cDNA library screening (CCLS) was used to examine gene expression in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung adenocarcinomas from (C3H/HeJ x A/J])F1 mice. Comparisons of RNA expression in lung adenocarcinomas to those of normal surrounding lung tissue revealed altered expression in 220 clones from more than 50,000 clones screened. Fifty clones were selected for quantitative reverse transcriptase-polymerase chain reaction (PCR) analysis to verify altered expression. PCR primers were designed based on partial sequence analysis of the clones. Twenty-two clones were found to be differentially expressed in lung adenocarcinomas compared with normal lungs. GenBank database analysis showed that 14 of the 22 clones were homologous with known genes, whereas 8 clones contained novel sequences. Thirteen clones were down regulated in tumors compared to normal lung tissues, and 9 were overexpressed. The clones underexpressed or absent include adipocyte p27, carbonic anhydrase III, carbonyl reductase, cytochrome CYP2E1, skelemin, myosin, major urinary protein, and contrapsin. Overexpressed clones include Bruton's tyrosine kinase, cyclin D3, poly(A)-binding protein, alpha-fetoprotein, transferrin, and mouse B2 family repetitive sequence. Further examination of biologic implications of the differentially expressed genes in lung adenocarcinomas is necessary to understand their role(s) in mouse lung carcinogenesis.
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PMID:Detection of differentially expressed genes in mouse lung adenocarcinomas. 1129 25


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