Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concentration of insulin-like growth factor I (IGF-I) in tissue taken from human non-small cell lung carcinomas (non-SCLC) is 1.4- to 7-fold higher than in the surrounding normal lung tissue, and thus, IGF-I may be involved in the growth of non-SCLC. We report here that non-SCLC cell lines (A549, A427, SK-LU-1) expressed the IGF-I receptor protein, and IGF-I stimulated the proliferation of low-density plated (2000 cells/cm2 growth area) carcinoma cells by 1.6- to 3-fold above control after a 4-day incubation period under serum-free conditions (A549, A427) or in the presence of 0.25% serum (SK-LU-1). Immunoblot data indicated that IGF-I was not secreted by the lung carcinoma cells; however, IGF-I-like proteins were present in the serum-free medium conditioned by human adult lung fibroblasts (CCD-19Lu). The secretion of the immunoreactive IGF-I-like protein was dependent on the passage level of the fibroblasts. At least one of the IGF-I-like factors promoted the serum-free growth of A549 cells (2-fold increase in cell number over control after 4 days) and stimulated a 3-fold increase in the tyrosine kinase activity of detergent-solubilized IGF-I receptors from A549 cells. Both stimulatory effects were neutralized by an anti-IGF-I antibody, suggesting that the fibroblast-derived factor mediated its activity via the IGF-I receptor. Our data indicate that lung fibroblast-derived IGF-I may stimulate the growth of non-SCLC in vivo.
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PMID:Insulin-like growth factor-I and human lung fibroblast-derived insulin-like growth factor-I stimulate the proliferation of human lung carcinoma cells in vitro. 839 25

The TRK-T1 oncogene, isolated from a human thyroid carcinoma, represents a rearranged form of the high affinity nerve growth factor (NGF) receptor encoded by the NTRK1 gene; it is created by an intrachromosomal rearrangement fusing the NTRK1 tyrosine kinase domain to the 5' portion of the TPR gene. We have investigated the effect of the TRK-T1 oncogene in PC12 cells, a model system for studying neuronal differentiation and the mechanism of action of NGF. Here, we report that, in PC12 cells, the TRK-T1 oncogene has a differentiating effect that resembles that of NGF and requires the phosphorylation of the oncoprotein. Our results are consistent with the hypothesis that TRK-T1, as well as the original TRK oncogene, induces PC12 differentiation by mimicking the action of NGF bound to its receptor.
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PMID:Expression of TRK-T1 oncogene induces differentiation of PC12 cells. 839 95

Early responses of mammalian cells to ionizing radiation include the activation of a protein kinase C implicated in the regulation of gene expression, the stimulation of tyrosine kinase activities, and the enhancement of phosphatidylinositol turnover. In the present report we show that clinically relevant doses of gamma-radiation (2 Gy) stimulate phosphatidylcholine hydrolysis in human squamous carcinoma cells. Radiation induced the accumulation of intracellular [3H]choline and the simultaneous increase in [3H]myristoyl-phosphatidic acid, followed by a small increase in the levels of [3H]myristoyl-diacylglycerol. Furthermore, in the presence of ethanol, gamma-radiation stimulated the appearance of [32P]phosphatidylethanol, an indicator of phospholipase D transphosphatidylation activity. These data demonstrate for the first time that phospholipase D activation participates in signaling pathways in response to gamma-radiation.
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PMID:Activation of phospholipase D participates in signal transduction pathways responsive to gamma-radiation. 840 16

Cell dispersion and motility are thought to be important steps in the invasion of tumor cells. The molecular mechanisms responsible for the induction of cell dispersion and motility remain unclear. Several factors affecting cell motility have been discovered. Among them, scatter factor (SF), a mesenchymal cell-derived protein, dissociates epithelial cell colonies into individual cells and stimulates the migration of epithelial cells. Purified SF promotes the invasiveness into collagen matrices of a number of human carcinoma cell lines, suggesting that SF is involved in the invasion of tumor cells. Recently, SF has been found to be identical to hepatocyte growth factor. Moreover, the c-met proto-oncogene product (the c-met protein) possessing a tyrosine kinase domain was identified as a receptor for SF. Three possible mechanisms have been postulated in which a tumor cell might increase its invasive potential through enhanced motility via SF and its receptor. First, in a cell already expressing the c-met protein, an unexpressed SF gene might be activated, leading to synthesis and secretion of the factor which could then initiate active motility in an autocrine fashion. Second, the tumor cell expressing the c-met protein may release a factor that affects surrounding mesenchymal cells, promotes synthesis and release of SF. The tumor cell would be stimulated in a paracrine fashion. Finally, the tumor cell may be exposed to SF already released by surrounding cells but may not be able to respond because it is partially or completely deficient in the c-met protein. Induction and increased expression of the c-met gene would result in the invasive phenotype of the tumor cell. Studies on these possible mechanisms will be required to elucidate the involvement of SF in the invasion of tumor cells.
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PMID:[Scatter factor and cell motility]. 843 87

Tumor necrosis factor (TNF) induces dose-dependent but incomplete cytotoxicity in ME-180 cervical carcinoma cells, suggesting that TNF response heterogeneity exists within this cell line. To investigate cellular properties associated with TNF-mediated cytotoxicity, ME-180 cell variants were isolated that stably expressed complete resistance (ME-180R) or sensitivity (ME-180S) to TNF and were compared to the parental cell line. Analysis of 125I-TNF binding on variant and parental cells provided evidence for postreceptor regulation of TNF responsiveness. Epidermal growth factor (EGF) receptor expression in TNF-resistant ME-180R cells was 3-fold higher than that expressed in the parental population and 4-fold higher when compared to TNF-sensitive ME-180S cells. High expression levels correlated with increased EGF receptor tyrosine kinase activity and receptor tyrosine phosphorylation. Southern and Northern blot analysis provided evidence of amplification and overexpression of the EGF receptor gene and its message in ME-180R cells which approached the content and alternate mRNA species expressed in A431 cells. Although 3-fold greater levels of total cellular EGF receptor protein were detected in ME-180R cell lysates, and its cell surface localization was confirmed by immunodetection, these cells were paradoxically unable to bind greater quantities of 125I-EGF or to express greater cytotoxic sensitivity to an EGF-diphtheria toxin fusion protein. Overall, these results suggest that expression of EGF receptor protein, its intrinsic tyrosine kinase activity, or its phosphotyrosine content may alter TNF cytotoxic signal transduction and control TNF responsiveness within the ME-180 cell line.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Epidermal growth factor receptor expression and function control cytotoxic responsiveness to tumor necrosis factor in ME-180 squamous carcinoma cells. 851 34

Ezrin is a component of the microvillus cytoskeleton of a variety of polarized epithelial cells and is believed to function as a membrane-cytoskeletal linker. In this study, we isolated microvilli from human placental syncytiotrophoblast as a model system for biochemical analysis of ezrin function. In contrast to intestinal microvilli, ezrin is a major protein component of placental microvilli, comprising approximately 5% of the total protein mass and present at about one quarter of the molar abundance of actin. Gel filtration and chemical cross-linking studies demonstrated that ezrin exists mainly in the form of noncovalent dimers and higher order oligomers in extracts of placental microvilli. A novel form of ezrin, apparently representing covalently cross-linked adducts, was present as a relatively minor constituent of placental microvilli. Both oligomers and adducts remained associated with the detergent-insoluble cytoskeleton, indicating a tight interaction with actin filaments. Moreover, stimulation of human A431 carcinoma cells with EGF induces the rapid formation of ezrin oligomers in vivo, thus identifying a signal transduction pathway involving ezrin oligomerization coincident with microvillus assembly. In addition to time course studies, experiments with tyrosine kinase and tyrosine phosphatase inhibitors revealed a correlation between the phosphorylation of ezrin on tyrosine and the onset of oligomer formation, consistent with the possibility that phosphorylation of ezrin might be required for the generation of stable oligomers. Based on these observations, a model for the assembly of cell surface structures is proposed.
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PMID:Ezrin oligomers are major cytoskeletal components of placental microvilli: a proposal for their involvement in cortical morphogenesis. 852 86

Radicicol, an inhibitor of protein-tyrosine kinase, was found to cause morphological reversion of v-Ha-ras-transformed NIH3T3 fibroblasts and T24 human urinary bladder carcinoma cells that contain an activated ras mutation. The network of actin stress fibers was restored during the treatment with radicicol. A similar morphological change was observed with another protein-tyrosine kinase inhibitor, herbimycin A. Radicicol did not cause any changes in the proportion of the active GTP binding form of p21ras or its subcellular localization. These results rule out the possibility that the morphological reversion by radicicol is due to direct or indirect inhibition of the p21ras function. Cycloheximide and actinomycin D inhibited the morphological change by radicicol, suggesting that the induced transcription of a gene(s) followed by de novo protein synthesis is required for suppression of the transformed phenotype in ras-transformed cells by tyrosine kinase inhibitors.
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PMID:Morphology of ras-transformed cells becomes apparently normal again with tyrosine kinase inhibitors without a decrease in the ras-GTP complex. 853 16

Growth factor receptors with tyrosine kinase activity mediate paracrine and autocrine growth regulation of normal and malignant cells. The epidermal growth factor receptor (EGF-R) is a tyrosine kinase transmembrane protein that is overexpressed by many epithelial malignancies, including transitional cell and renal cell carcinoma. Ligand-induced stimulation of cell growth depends on activation of the tyrosine kinase activity of the EGF-R. Tyrphostins are small molecular weight compounds that have been shown to preferentially inhibit the EGF-R tyrosine kinase and thus may inhibit EGF-R-dependent cell growth. We examined the effect of two tyrphostins, RG14620 and AG555, on the proliferation of three transitional cell carcinoma lines (RT4, J82, and T24) and three renal cell carcinoma lines (A-198, Caki-1, and Caki-2). Both tyrphostins inhibited proliferation of all six cell lines in a dose-dependent fashion. They were equally effective with IC50s ranging between 3 and 16 microM. Complete inhibition of growth was achieved at tyrphostin concentrations between 10 and 30 microM. Although both tyrphostins inhibited proliferation of T24 transitional carcinoma cells in growth assays, only RG14620 but not AG555 was found to specifically inhibit EGF-R autophosphorylation in this cell line. These results suggest that other intracellular targets in addition to the EGF-R are affected by these agents. In summary, tyrphostins are potent growth inhibitors for urological malignancies.
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PMID:Antiproliferative effects of tyrosine kinase inhibitors (tyrphostins) on human bladder and renal carcinoma cells. 853 64

The transformation of the normal fully differentiated thyroid follicular cell to the rapidly growing undifferentiated anaplastic thyroid carcinoma cell involves a number of stages which have been defined morphologically and are now being related to various growth pathways and to molecular biological defects. The two main factors involved in this transformation are growth stimulation and mutagenesis. Growth stimulation alone, through elevated TSH, can lead to the development of thyroid tumours, usually benign, and retaining TSH dependency in some cases. Mutagens alone, if growth is suppressed, do not produce tumours, the combination of mutagens and increased growth is a potent carcinogenic regime. Non-genotoxic carcinogenesis in the thyroid involves growth, without mutagenesis the agent often causes this through affecting one component of thyroid hormone synthesis or metabolism, leading to a fall in thyroid hormone levels and a rise in TSH. Growth stimulation increases the rate of cell division, and therefore increases the chance of a mutation. Continued growth increases the change of subsequent events, in particular loss of heterozygosity in a tumour suppressor gene. The main oncogenes involved in human thyroid carcinogens are ras in the follicular tumour pathway, and ret in the papillary carcinoma pathway. p53 is involved in the progression of either papillary or follicular adenoma to an undifferentiated carcinoma. In experimental thyroid carcinogenesis, ras is again involved, with a link between the mutagenic agent used and the type of ras gene showing mutation. Analysis of the involvement of different growth factors and oncogenes in thyroid carcinogenesis suggests that genes related to the two receptors concerned with normal TSH stimulated growth, TSH receptor and the IGF1 receptor may be involved in the progression of thyroid tumours of follicular pathology. Several tyrosine kinase receptors with unknown ligands or of uncertain physiological function are linked to papillary carcinoma. The recent large increase in papillary carcinoma of the thyroid in children exposed to fallout from the Chernobyl nuclear accident underlines the importance of understanding the pathobiology of thyroid neoplasia.
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PMID:Mechanisms and pathogenesis of thyroid cancer in animals and man. 853 19

Recent studies have established that the ret protooncogene is involved in the development of thyroid tumors, including medullary and papillary thyroid carcinomas. Germ line mutations of the ret protooncogene were identified in multiple endocrine neoplasia (MEN) types 2A and 2B that share the clinical feature of medullary thyroid carcinoma and pheochromocytoma. MEN 2A mutations involved cysteine residues in the extracellular domain and induced disulfide-linked homodimerization of the Ret protein on the cell surface, leading to activation of its intrinsic tyrosine kinase. On the other hand, a single point mutation in the tyrosine kinase domain was found in MEN 2B, as well as in 30 to 40% of sporadic medullary carcinoma. This mutation also resulted in activation of Ret tyrosine kinase without the formation of its covalent homodimerization. Differences in the mechanisms of ret activation might account for the different phenotypes observed in MEN 2A and MEN 2B. In addition, somatic rearrangement of the ret protooncogene was frequently detected in papillary thyroid carcinoma, particularly from adult Europeans. A recent report demonstrated that the same rearrangement was observed in approximately 60% of papillary carcinomas of children from areas contaminated by the Chernobyl accident, suggesting that ret rearrangement was induced as a direct consequence of radiation exposure. In this review, I focus on the ret mutations detected in thyroid cancer and discuss the mechanisms of its oncogenic activation.
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PMID:Oncogenic activation of the ret protooncogene in thyroid cancer. 857 6


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