Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001418 (adenocarcinoma)
 68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The density of the alpha 2A-adrenergic receptor in the HT29 cell line, a human colonic adenocarcinoma, increases when the cells are placed in fetal calf serum (FCS)-free culture medium and decreases again, in a concentration-dependent manner, when they are re-exposed to FCS. In an attempt to identify the FCS components responsible for this phenomenon, we examined the effect of insulin and of various growth factors on receptor expression. Incubation of HT29 cells with insulin resulted in a time- and dose-dependent lowering of the alpha 2-adrenergic receptor number. The decrease of [3H] RX821002 binding sites after a 48-h period of treatment reached 70-75% with 170 nM insulin, and a half-maximal effect was observed at 2.6 nM. This value is in agreement with the EC50 of the hormone for stimulating the glycolytic activity of HT29 cells (8 nM) and is sufficiently low to indicate that the decrease of alpha 2-adrenergic receptor number is mediated through stimulation of insulin receptors. Direct quantification of [3H] UK14304 binding sites and the study of the inhibition of [3H]RX821002 binding by (-)-epinephrine indicated that the degree of receptor coupling to Gi protein was not affected when the receptor number was decreased by insulin treatment. The reduction in receptor number did result in an attenuation of the inhibitory effect of UK14304 on forskolin-induced cAMP accumulation in a manner which was consistent with the existence of a large population of spare receptors in untreated cells. The action of insulin is not due to an accelerated rate of receptor degradation and can be mimicked by other growth factors (epidermal growth factor and insulin-like growth factors I and II) acting through stimulation of tyrosine kinase receptors. RNase mapping experiments with a 0.35-kilobase riboprobe prepared from the human alpha 2 C10-adrenergic receptor gene demonstrated that the decrease of receptor number induced by the different treatments is a reflection of changes occurring at the level of its mRNA. The use of cycloheximide indicated that the effect of insulin on alpha 2-adrenergic receptor mRNA does not require protein synthesis. The half-life of the alpha 2-adrenergic receptor mRNA measured after the addition of actinomycin D was unchanged by insulin which suggests that a decrease in the transcription rate is the predominant factor responsible for the observed regulation of receptor expression.
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PMID:Regulation of the alpha 2A-adrenergic receptor in the HT29 cell line. Effects of insulin and growth factors. 167 44

The effect of herbimycin A, an ansamycin antibiotic which inhibits cellular transformation by retroviral tyrosine kinases, on the monolayer growth of seven colon tumor cell lines and one cell line established from normal colonic mucosa, CCL239, was examined. Each colon tumor cell line tested showed dose-dependent growth inhibition in response to herbimycin A. A 125ng ml-1 dose of the antibiotic caused greater than 40% growth inhibition in all colon tumor cell lines after two cell doublings. In contrast, at similar herbimycin A concentrations only 12% inhibition was observed in 'normal' CCL239 cells. No major morphologic changes were observed at the light microscopic level in any of the tumor cell lines or CCL239 cells in response to treatment with herbimycin A. Studies using the HT29 colon adenocarcinoma cell line showed dose-dependent inactivation of pp60c-src by herbimycin A, resulting in decreased autophosphorylation, enolase phosphorylation and steady-state levels, which correlated with cellular growth inhibition. Herbimycin A-induced reductions in pp60c-src kinase activity preceded changes in pp60c-src steady-state levels. Growth and pp60c-src inhibition were reversible following removal of herbimycin A from cell culture media. Our results suggest that regulation of pp60c-src tyrosine kinase activity may be important in growth control of colon tumor cells.
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PMID:Effect of herbimycin A on growth and pp60c-src activity in human colon tumor cell lines. 171 64

p185neu is the protein product of the HER2/neu protooncogene. This protein has characteristics of a tyrosine kinase growth factor receptor and is postulated to be important in human carcinogenesis. To define the significance of the expression of this protein in human non-small cell lung cancer, 55 tumors from patients with squamous cell carcinoma (16), adenocarcinoma (29), or large cell carcinoma (10) of the lung were examined for p185neu using immunohistological methods. Five of 16 squamous cell carcinomas and 10 of 29 adenocarcinomas were found to overexpress p185neu relative to levels of expression seen in uninvolved bronchiolar epithelium. For the adenocarcinomas, p185neu expression was associated with older age (66.6 +/- 10.1 versus 57.5 +/- 10.8 years) (P = 0.04) and shortened survival (83.7 +/- 94.1 versus 188.5 +/- 120 weeks) (P = 0.01). In this group, using Cox's multivariate survival analysis, p185neu expression was found to be a significant determinant of survival (P = 0.04) even after accounting for the effect of tumor stage. For the squamous cell carcinomas, p185neu expression was not correlated with any of our clinicopathological parameters. Our findings indicate that non-small cell lung cancers which express p185neu do so at levels higher than that found in normal bronchiolar epithelium, and expression in adenocarcinomas of the lung is independently associated with diminished survival intervals.
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PMID:p185neu expression in human lung adenocarcinomas predicts shortened survival. 197 68

Microvilli isolated from the MAT-C1 ascites subline of the 13762 rat mammary adenocarcinoma contain a major calcium-sensitive microfilament-binding protein, AMV-p35 (ascites microvillar p35). Association of AMV-p35 with microfilament cores during Triton X-100 extraction of the microvilli is half-maximal at 0.1-0.2 mM calcium. The protein, which comprises 6% of the total microvillar protein, can be isolated from microfilament cores prepared in the presence of calcium by extraction with EGTA and purification by ion-exchange chromatography. Alternatively, the protein can be isolated from Triton extracts of microvilli prepared in the absence of calcium by precipitation with calcium, solubilization of the precipitate with EGTA, and chromatography on an ion-exchange column. AMV-p35 binds to phosphatidylserine liposomes and F-actin with half-maximal calcium concentrations of about 10 microM and 0.2 mM, respectively. Treatment of AMV-p35 with chymotrypsin yields a 33,000-dalton fragment, behavior similar to the tyrosine kinase substrates calpactins I and II and lipocortins I and II. Immunoblot analyses using antibodies directed against calpactin I, lipocortin I, and lipocortin II showed strong reactivity of AMV-p35 with anti-calpactin I and anti-lipocortin II, but little reactivity toward anti-lipocortin I. The close relationship between AMV-p35 and calpactin I was verified by amino acid sequence analyses of peptides isolated from cyanogen bromide digests of AMV-p35. By gel filtration and velocity sedimentation analyses purified AMV-p35 is a 35,000-dalton monomer. Moreover, AMV-p35 extracted directly from microvilli in Triton/EGTA also behaves as a 35,000-dalton menomer. These findings indicate that AMV-p35 is closely related to the pp60src kinase substrate calpactin I (p36). However, AMV-p35 occurs in the microvilli as a monomer rather than as the heterotetrameric calpactin found in several other cell types.
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PMID:Isolation of a calcium-sensitive, 35,000-dalton microfilament- and liposome-binding protein from ascites tumor cell microvilli: identification as monomeric calpactin. 296 74

Antibodies were raised against a synthetic peptide corresponding to 14 amino acid residues at the COOH-terminus of a protein deduced from the human c-erbB-2 nucleotide sequence. These antibodies immunoprecipitated a 185-kilodalton glycoprotein from MKN-7 adenocarcinoma cells. Incubation of the immunoprecipitates with (gamma-32P)ATP resulted in the phosphorylation of this protein on tyrosine residues. These results indicate that the human c-erbB-2 gene product is the 185-kilodalton glycoprotein that is associated with tyrosine kinase activity. Although the c-erbB-2 protein was predicted to encode a protein very similar to epidermal growth factor (EGF) receptor, EGF did not stimulate this kinase activity either in vivo or in vitro.
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PMID:The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. 301 81

Insulin binding and receptor tyrosine kinase activity were investigated in the insulin-responsive R3230AC mammary adenocarcinoma. Insulin receptors, partially purified by wheat germ agglutinin-agarose chromatography, displayed electrophoretic properties similar to those of normal tissues and demonstrated autophosphorylation of the beta subunit. Tyrosine kinase activity of tumor preparations was measured by incorporation of 32P from ATP into the synthetic polypeptide substrate glutamic acid80:tyrosine20. The Km (app) for ATP, 15 to 30 microM in tumors from ovariectomized or intact rats, appeared to be increased by 10(-7) M insulin in vitro, with the calculated Vmax increased by 3- to 5-fold; the Km (app) for glutamic acid80:tyrosine20 was 2 to 3 microM and insulin increased the Vmax by 25 to 50%. The effects of diabetes and insulin treatment and of various doses of estradiol, progesterone, estradiol plus progesterone, or tamoxifen on insulin binding, basal tyrosine kinase activity, and insulin-inducible tyrosine kinase activity in vitro were studied in tumors from treated animals. Preparations from diabetic rats had elevated insulin binding and basal tyrosine kinase activity and displayed a striking dose-related increase in the ability for insulin induction of tyrosine kinase activity in vitro compared to intact animals; these effects of diabetes were prevented by administration of insulin. Over comparable doses, insulin growth factor 1 added in vitro induced tyrosine kinase activity minimally versus that seen for insulin. Treatment of rats with pharmacological doses of sex steroid hormones produced changes in insulin binding capacity and/or basal tyrosine kinase activity and, depending on dose, usually resulted in increased basal kinase activity relative to insulin binding. The insulin-inducible increase in tyrosine kinase activity in vitro was not altered by treatment with estradiol or estradiol plus progesterone in vivo, whereas high doses of progesterone attenuated the response. A consistent finding with increasing doses of sex steroids was an increase in the half-maximum dose or 50% maximum induction dose for insulin, implying reduced responsiveness. Tamoxifen administered to intact rats increased insulin binding and blunted the insulin-induced increase in tyrosine kinase in vitro; these effects were not seen in ovariectomized rats...
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PMID:Effects of diabetes and sex steroid hormones on insulin receptor tyrosine kinase activity in R3230AC mammary adenocarcinomas. 328 34

We recently reported that tyrphostin 23 (3,4-dihydroxybenzylidene malononitrile) is unstable in solution and that some of the degradation products are better inhibitors of the tyrosine kinase activity of Src and the EGF-receptor kinase than the parent compound itself (Ramdas et al., Cancer Res. 54, 867-868, 1994). In this study, the tyrphostin 23-derived compound designated P3, which is a more stable and potent protein tyrosine kinase inhibitor, was isolated. P3 was purified from oxidized tyrphostin 23 by solvent extraction, silica-gel flash chromatography, and reverse-phase high-pressure liquid chromatography. The physical characteristics of the isolated compound were determined and its chemical structure elucidated by 1H and 13C NMR spectroscopy. The proposed structure of this new inhibitor is that of a tyrphostin 23 dimer joined at the benzylidene carbon. P3 was evaluated in vitro as an inhibitor of four different protein tyrosine kinases (Src, Csk, EGF-receptor, and FGF-receptor) and two protein serine kinases (PK-A and PK-C). This compound exhibited the most inhibitory activity against Src with a Ki value of 6 microM and was less inhibitory toward the other protein kinases with Ki values ranging from 35 to 300 microM. P3 did not inhibit other nucleotide-utilizing enzymes such as lactate dehydrogenase and hexokinase. The growth and colony formation of HT-29 colon adenocarcinoma cells that contain activated Src was inhibited by P3 with an IC50 value of approximately 10 microM.
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PMID:A tyrphostin-derived inhibitor of protein tyrosine kinases: isolation and characterization. 748 83

Activated pp60c-src has been implicated in a number of human malignancies including colon carcinoma and breast adenocarcinoma. Association of the src SH2 domain with tyrosine-phosphorylated proteins plays a role in src-mediated signal transduction. Inhibitors of src SH2 domain-phosphoprotein interactions are, thus, of great interest in defining the role(s) of src in signal transduction pathways. To facilitate such studies, an enzyme-linked immunosorbent assay (ELISA) was developed to detect inhibitors of src SH2-phosphoprotein interactions. This assay measures inhibition of binding of a fusion construct (glutathione S-transferase src SH3-SH2) with autophosphorylated epidermal growth factor receptor tyrosine kinase domain. Activities of phosphopeptide segments derived from potential src SH2 cognate phosphoprotein partners were determined, with the focal adhesion kinase-derived segment VSETDDY*AEIIDE yielding the highest inhibitory activity. Structure activity studies starting from acetyl (Ac)-Y*EEIE have identified Ac-Y*Y*Y*IE as the most active compound screened in the ELISA. This compound is at least 20-fold more active than the parent peptide Ac-Y*EEIE. A high resolution (2 A) crystal structure of human src SH2 complexed with Ac-Y*EEIE was obtained and provided a useful framework for understanding the structure-activity relationships. Additionally, Ac-Y*EEIE was able to block interactions between src and its cellular phosphoprotein partners in vanadate-treated cell lysates from MDA-MB-468 breast carcinoma cells. However, it is unable to abrogate proliferation of MDA-MB-468 cells in culture, presumably because of poor cell penetration and/or lability of the phosphate group on tyrosine.
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PMID:Peptide inhibitors of src SH3-SH2-phosphoprotein interactions. 752 93

To understand the genes and gene products involved in breast cancer invasion and metastasis, we previously isolated ten differentially expressed genes by differential cDNA library screening techniques, using the 13762NF rat mammary adenocarcinoma metastatic system. In this study, we further analysed a novel candidate metastasis-associated gene, mta1, previously designated clone 10.14. Northern blotting analyses showed that the steady-state mRNA expression level of mta1 was fourfold higher in a highly metastatic line (MTLn3) than in a nonmetastatic line (MTC.4). The mta1 gene was expressed at low levels in various normal rat organs, except testis, where it was expressed in high amounts. The mRNA expression levels of the human homologue of this gene were also examined in two human breast cancer metastatic systems; the ratios of mRNA were estimated to be MCF-7 (nonmetastatic):MCF7/LCC1 (invasive):MCF7/LCC2 (metastatic) = 1:2:4 and MDA-MB-468 (nonmetastatic):MDA231 (metastatic) = 1:4. Thus, the expression of this gene directly correlated with metastatic potential in two human systems, as well as in the rat metastatic system. Clone 10.14 was used to isolate a full-length cDNA clone for mta1, yielding the clone p10.14-C4.5, which was sequenced and analysed. Clone p10.14-C4.5 was 2756-bp long and contained a single open reading frame that could encode a protein of 703 amino acid (aa) residues. The aa sequence of mta1 was found to be novel by database homology search and contained possible phosphorylation sites for tyrosine kinase, protein kinase C and casein kinase II. A Pro-rich stretch was found at the C-terminal end that completely matched the consensus sequence for the SH3-binding motif.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of the complete sequence of the novel metastasis-associated candidate gene, mta1, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. 760 77

A series of benzylidenemalononitrile derivatives previously synthesized by condensing aromatic aldehydes with malononitrile derivatives are known as tyrphostins. In this study, 32 tyrphostins were synthesized, 19 of which are novel compounds. Both hydroxylated derivatives and compounds containing heteroaromatic moieties were prepared. We have confirmed and extended the observation that the tyrphostins displayed an enhancement in their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase domain as the number of hydroxyl groups on the aromatic portion was increased. IC50 values of 1-5 microM were readily achieved. Some inhibitory activity was seen with the heteroaromatic structures, with two compounds exhibiting IC50 values of 56 and 77 microM. However, these derivatives were poor inhibitors of the EGF receptor tyrosine kinase activity as compared to the hydroxylated derivatives. The ability of the 32 tyrphostins synthesized in the present study to inhibit proliferation of a human breast adenocarcinoma cell line (MCF-7) was determined using [3H]thymidine incorporation as a measure of DNA synthesis. Some of the compounds containing pyridine, imidazole or thiophene portions displayed antiproliferative activity comparable to that of tyrphostins prepared from 3,4,5-trihydroxybenzaldehyde. The lack of inhibitory effect of these heteroaromatic compounds on the EGF receptor tyrosine kinase activity suggests that their antiproliferative activity is not related to inhibition of EGF receptor function. As the growth of the MCF-7 cell line is governed by other factors, such as the insulin-like growth factors (IGFs) and oestradiol, it is also still to be established whether the antiproliferative activity of the hydroxylated tyrphostins is directly related to inhibition of the EGF receptor tyrosine kinase activity.
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PMID:Synthesis and antiproliferative activity of tyrphostins containing heteroaromatic moieties. 791 98


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