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Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis.
Nørgaard P, Law B, Joseph H, Page DL, Shyr Y, Mays D, Pietenpol JA, Kohl NE, Oliff A, Coffey RJ, Poulsen HS, Moses HL
(1999) Clin Cancer Res 5: 35-42
MeSH Terms: Alkyl and Aryl Transferases, Animals, Apoptosis, Calcium-Calmodulin-Dependent Protein Kinases, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Farnesyltranstransferase, Female, G1 Phase, Growth Inhibitors, Mammary Neoplasms, Experimental, Methionine, Mice, Mice, Transgenic, Receptor, ErbB-2, Transforming Growth Factor alpha
Show Abstract · Added February 17, 2014
Mouse mammary tumor virus-transforming growth factor alpha (MMTV-TGF alpha) and MMTV-TGF alpha/neu transgenic mice develop mammary tumors after a long latency and therefore provide useful model systems for breast cancer with its recognized activation of receptor tyrosine kinase signaling. We used these mice to study the antitumor effect of L-744,832 (FTI), a potent and selective inhibitor of farnesyl-protein transferase, and hence of Ras function. A total of 55 mice were assigned randomly to treatment with FTI or vehicle, and one-half of the mice were crossed over after initial treatment to the opposite group. L-744,832 induced reversible regression of mammary tumors that was paralleled by a decrease in serum levels of TGF alpha secreted by the tumor cells. There was no difference in response to treatment with FTI between MMTV-TGF alpha mice, in which tumorigenesis was accelerated by multiparity or the chemical carcinogen 7,12-dimethylbenzanthracene, and MMTV-TGF alpha/neu mice. The tumor histological type had no impact on FTI sensitivity. For mechanistic analyses, tumor excision biopsies were obtained from 12 mice before and after treatment with L-744,832. In these samples, tumor regression was paralleled biochemically by inhibition of mitogen-activated protein kinase activity and biologically by an increase in G1-phase and decrease in S-phase fractions, as well as induction of apoptosis. These results suggest that the potential clinical use of FTI could be expanded to include cancers harboring activated receptor tyrosine kinases as well as those containing activated Ras.
1 Communities
3 Members
0 Resources
16 MeSH Terms
Regulation of rhTNF in abdominal cavity to the expression of C-erbB-2 of ovarian cancer nude mice ascites tumor.
Yin D, Zhang X, Feng Y, Cao B, Li W, Qian H, Fu T, Wu Z
(1997) Chin Med J (Engl) 110: 311-2
MeSH Terms: Animals, Cystadenocarcinoma, Papillary, Female, Flow Cytometry, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Ovarian Neoplasms, Receptor, ErbB-2, Recombinant Proteins, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Added December 10, 2013
0 Communities
1 Members
0 Resources
14 MeSH Terms
Unliganded epidermal growth factor receptor dimerization induced by direct interaction of quinazolines with the ATP binding site.
Arteaga CL, Ramsey TT, Shawver LK, Guyer CA
(1997) J Biol Chem 272: 23247-54
MeSH Terms: Adenosine, Adenosine Triphosphate, Adenylyl Imidodiphosphate, Binding Sites, Carrier Proteins, Dimerization, Enzyme Inhibitors, ErbB Receptors, Glycoproteins, Humans, Ligands, Neuregulin-1, Nitriles, Phosphorylation, Protein Binding, Protein Conformation, Quinazolines, Receptor, ErbB-2, Signal Transduction, Tumor Cells, Cultured, Tyrphostins
Show Abstract · Added March 5, 2014
Receptor dimerization is critical for signaling by the epidermal growth factor receptor (EGFR) tyrosine kinase. This occurs after binding of the receptor's extracellular domain by ligand or bivalent antibodies. The role of other receptor domains in dimerization is less clear, and there are no examples of dimers induced by direct perturbation of the EGFR kinase domain. Submicromolar concentrations of AG-1478 and AG-1517, quinazolines specific for inhibition of the EGFR kinase, induced reversible receptor dimerization in vitro and in intact A431 cells. Consistent with the inhibitory effect of quinazolines on receptor kinase activity, the dimers formed lacked a detectable Tyr(P) signal. Quinazoline-induced EGFR dimerization was abrogated in vitro by ATP and the ATP analog adenyl-5'-yl imidodiphosphate. Receptors with a single-point mutation in the ATP binding site as well as wild-type EGFR with a covalent modification of the ATP site failed to dimerize in response to AG-1478 and AG-1517. These data suggest that EGFR dimerization can be induced by the interaction of quinazolines at the ATP site in the absence of receptor ligand binding. In SKBR-3 cells, the quinazolines induced the formation of inactive EGFR/ErbB-2 heterodimers, potentially sequestering ErbB-2 from interacting with other coreceptors of the ErbB family. Structural studies of the quinazoline interaction with the EGFR tyrosine kinase domain should allow for an analysis of receptor-specific chemical features required for binding to the ATP site and disruption of signaling, a strategy that can be perhaps applied to other tumor cell receptor systems.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Epidermal growth factor stimulates substrate-selective protein-tyrosine-phosphatase activity.
Hernández-Sotomayor SM, Arteaga CL, Soler C, Carpenter G
(1993) Proc Natl Acad Sci U S A 90: 7691-5
MeSH Terms: 3T3 Cells, Animals, Carcinoma, Squamous Cell, Cytosol, Epidermal Growth Factor, ErbB Receptors, GTP-Binding Proteins, Humans, Isoenzymes, Kinetics, Mice, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptor, ErbB-2, Substrate Specificity, Tumor Cells, Cultured, Type C Phospholipases, rap GTP-Binding Proteins
Show Abstract · Added March 5, 2014
This study investigates the regulation of protein-tyrosine-phosphatase (PTPase; EC 3.1.3.48) activity by epidermal growth factor (EGF). Cytosol from EGF-treated A-431 human epidermoid carcinoma cells was used as a source of PTPase activity, and tyrosine-phosphorylated ErbB2, EGF receptor, phospholipase C-gamma 1, and the Ras GTPase-activating protein were used as substrates to monitor PTPase activity. EGF stimulated PTPase activity that was selective toward these substrates, as it dephosphorylated ErbB2 and the EGF receptor, but not phospholipase C-gamma 1 and the Ras GTPase-activating protein. EGF stimulated PTPase activity in several cell lines, regardless of EGF receptor number, and the activity was localized in the cytosol. The dephosphorylation activity in vitro was dependent on the presence of reducing agents and was inhibited by orthovanadate. Agonists such as phorbol 12-myristate 13-acetate, isoproterenol, or ATP were unable to stimulate PTPase activity. Physiological relevance is indicated by experiments showing that EGF treatment of a human mammary cancer cell line rapidly induced the dephosphorylation of ErbB2.
0 Communities
1 Members
0 Resources
19 MeSH Terms
p185c-erbB-2 signal enhances cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an oncogenic receptor tyrosine kinase and drug-induced DNA repair.
Arteaga CL, Winnier AR, Poirier MC, Lopez-Larraza DM, Shawver LK, Hurd SD, Stewart SJ
(1994) Cancer Res 54: 3758-65
MeSH Terms: Antibodies, Monoclonal, Breast Neoplasms, Cisplatin, DNA Repair, ErbB Receptors, Female, Humans, Phosphorylation, Protein Kinase C, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Receptor, ErbB-2, Signal Transduction, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
The c-erbB-2 (HER-2/neu) protooncogene encodes an M(r) 185,000 transmembrane glycoprotein with intrinsic tyrosine kinase activity. Agonistic antibodies against p185c-erbB-2 enhance the cytotoxic effect of the DNA alkylator, cisplatin, against c-erbB-2-overexpressing human carcinoma cells (Hancock et al., Cancer Res., 51:4575-4580, 1991). We have studied the possible association between receptor signal transduction and cisplatin-mediated cytotoxicity utilizing the SKBR-3 human breast cancer cell line and the anti-p185 TAb 250 IgG1. TAb 250 induced tyrosine phosphorylation of p185 and the receptor substrate phospholipase C-gamma 1, as well as rapid association of these molecules in vivo. Simultaneously with phosphorylation, phospholipase C-gamma 1 catalytic activity measured in a [3H]phosphatidylinositol-4,5-bisphosphate hydrolysis assay was increased 61 +/- 12% above control. Preincubation of SKBR-3 cells with the tyrosine kinase inhibitor tyrphostin 50864-2 abrogated the enhancement of drug-mediated cell kill induced by TAb 250. The supraadditive drug/antibody effect was not seen in SKBR-3 cells with TAb 263, an anti-p185 IgG1 that does not induce receptor signaling or with TAb 250 in MDA-468 breast cancer cells which do not overexpress c-erbB-2. In addition, transforming growth factor-alpha increased cisplatin-induced cytotoxicity against NIH 3T3 cells overexpressing an epidermal growth factor receptor/c-erbB-2 chimera. Cellular uptake or efflux of [195mPt]cisplatin by SKBR-3 cells was not altered by TAb 250. Finally, simultaneous treatment of SKBR-3 cells with TAb 250 and cisplatin increased cisplatin/DNA intrastrand adduct formation and delayed the rate of adduct decay. Taken together these data support a direct association between p185c-erbB-2 signal transduction and inhibition of cisplatin-induced DNA repair.
0 Communities
1 Members
0 Resources
14 MeSH Terms
C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas.
Kern JA, Slebos RJ, Top B, Rodenhuis S, Lager D, Robinson RA, Weiner D, Schwartz DA
(1994) J Clin Invest 93: 516-20
MeSH Terms: Actuarial Analysis, Adenocarcinoma, Age Factors, Base Sequence, Biomarkers, Tumor, DNA Primers, DNA, Neoplasm, ErbB Receptors, Female, Genes, ras, Humans, Lung Neoplasms, Male, Molecular Sequence Data, Multivariate Analysis, Neoplasm Staging, Point Mutation, Polymerase Chain Reaction, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins, Proto-Oncogenes, Receptor, ErbB-2, Risk Factors, Survival Analysis, Time Factors
Show Abstract · Added March 5, 2014
We evaluated the prognostic significance of p185c-erbB-2 expression and ras gene mutations in all patients diagnosed with a pulmonary adenocarcinoma between 1982 and 1985 at the University of Iowa. p185c-erbB-2 expression was detected in 15 cases (34%). A ras gene mutation was found in 16 cases (36%) and all were in codon-12 of K-ras. No N-ras mutations were identified. Both p185c-erbB-2 expression and a K-ras mutation were found only in codon-12 and present in six cases (14%). By univariate analysis p185c-erbB-2 expression was associated with shortened survival (P = 0.02) while the presence of a K-ras mutation was not (P = 0.16). Multivariate analysis by the Cox proportional hazards model, controlling for patient age and tumor stage, also continued to identify p185c-erbB-2 expression as an independent unfavorable prognostic factor (P = 0.01). In this model a K-ras mutation also approached significance as a poor prognostic indicator (P = 0.06). The impact of both p185c-erbB-2 expression and a K-ras mutation on survival was additive and highly significant (P = 0.004). This additive nature suggests that together these two markers identify a high-risk population of lung adenocarcinoma patients that may benefit from aggressive therapy.
0 Communities
1 Members
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26 MeSH Terms
Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas.
Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL
(1991) Proc Natl Acad Sci U S A 88: 10435-9
MeSH Terms: Amino Acid Sequence, Biomarkers, Tumor, Breast, Breast Neoplasms, Carcinoma, ErbB Receptors, Female, Fibrocystic Breast Disease, Humans, Immune Sera, Immunoblotting, Immunohistochemistry, Isoenzymes, Molecular Sequence Data, Peptides, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptor, ErbB-2, Reference Values, Substrate Specificity, Type C Phospholipases
Show Abstract · Added March 5, 2014
Phospholipase C-gamma 1 (PLC-gamma 1) is a substrate for several receptor tyrosine kinases and its catalytic activity is increased by tyrosine phosphorylation. However, the biological significance of this molecule in normal or malignant human epithelial cell proliferation is unknown. We determined the relative content of PLC-gamma 1 in primary human mammary carcinomas and in nonmalignant mammary tissues. By Western blot and immunohistochemistry, considerably higher levels of PLC-gamma 1 protein were detectable in the majority of carcinomas and in one of two benign fibroadenomas compared to normal breast tissues. In 18 of 21 carcinomas that contained high levels of PLC-gamma 1, the presence of phosphotyrosine on PLC-gamma 1 could also be detected. All carcinomas in which tyrosine phosphorylated PLC-gamma 1 was present also expressed detectable levels of the epidermal growth factor receptor or erbB-2, two tyrosine kinases known to phosphorylate this enzyme. Thus, a high percentage of mammary carcinomas concomitantly display increased levels of receptor tyrosine kinases and a direct tyrosine phosphorylation substrate, thereby potentially amplifying two successive steps in a signal transduction pathway.
1 Communities
2 Members
0 Resources
21 MeSH Terms