Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human breast carcinoma cell line SK-BR-3, expresses the neu oncogene product, p185, which is a receptor tyrosine kinase. Using a double monoclonal antibody capture enzyme-linked immunosorbent assay for p185, activity was detected in conditioned media from cultures of SK-BR-3 cells. Two monoclonal antibodies specific for the extracellular domain of p185/neu immunoprecipitated a protein with a molecular mass of approximately 105 kDa. p105 was further shown to compete with p185 for binding to monoclonal antibodies and pulse-chase experiments indicate that it was generated by post-translational processing. Peptide maps showed that p105 and p185 are related polypeptides. Since p105 is close to the predicted size for the extracellular domain of p185/neu, we propose that SK-BR-3 cells specifically process and release this portion of the receptor into the medium. The release of the extracellular domain may have implications in oncogenesis and its detection could prove useful as a cancer diagnostic.
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PMID:The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3. 167 Oct 42

Genetic and molecular analyses of Drosophila have shown that tumorigenesis may arise from inactivation of single genes controlling cell growth and differentiation. Recessive mutations in a series of genes interrupt the differentiation of primordial cells and result in overgrowth, producing either hyperplasia or neoplasia. In mutant animals tumours form in either the optic centres of the larval brain, the imaginal discs or the haemopoietic organs. In Drosophila 17 genetic loci giving rise to neoplasia and six loci producing hyperplasia have been identified. The lethal(2)giant larvae gene constitutes the prototype of these genes. Its molecular cloning and analysis have demonstrated that the tumor phenotype results from a lack of gene function. Furthermore, tumour prevention was achieved by introducing a normal copy of l(2)gl into the genome of l(2)gl- deficient animals, showing that the l(2)gl gene behaves as a tumour suppressor or anti-oncogene. Melanomas of genetic origin develop in interspecies hybrids of the fish Xiphophorus. The melanoma appears when a sex linked chromosomal gene (Tu) is present among the progeny animals lacking an autosomal locus Differentiation, which acts as a tumour suppressor gene. A sequence homologous to the erb-B gene can be associated to the sex chromosomal Tu locus. This gene encodes a receptor tyrosine kinase related to the EGF-receptor, and its activation and overexpression are thought to play a critical part in melanoma formation.
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PMID:The fruit fly Drosophila and the fish Xiphophorus as model systems for cancer studies. 210 23

Activation of the EGF receptor (c-erbB) tyrosine kinase has been implicated in tumorigenesis, either by overexpression of the normal receptor in the presence of EGF, or through expression of a truncated receptor lacking the EGF binding domain as in the viral oncogene v-erbB. Here, normal and truncated human EGF receptors expressed in Rat1 fibroblasts were analysed for receptor tyrosine kinase activity and several transformation parameters in comparison with polyoma middle T and EJ-ras. Expression of a truncated EGF receptor lacking the extracellular ligand binding domain induced transformation of immortalized rodent fibroblasts and appears to activate the intrinsic tyrosine kinase. The transformed phenotype becomes enhanced by further truncation of the C-terminal domain containing the tyrosine autophosphorylation sites P1 and P2. Over expression of EGF receptors with an intact extracellular region in transfected Rat1 cells shows EGF dependent transformation, which is reduced by C-terminal truncation. Transformation is dependent on the cellular receptor concentration and can be selected as a stable phenotype. We conclude that expression of receptors with a truncated EGF-binding domain alone is sufficient to transform mammalian fibroblasts, in contrast to chick fibroblasts transformed by v-erbB where additional deletion of C-terminal receptor sequences appears to be an absolute requirement.
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PMID:Analysis of mammalian fibroblast transformation by normal and mutated human EGF receptors. 278 50

Angiogenesis, the process by which new blood vessels are formed, is essential in reproduction, development, wound repair and oncogenesis. Endothelial receptor tyrosine kinases are likely to play key roles in the intercellular signalling controlling angiogenesis. We have here analysed the expression of the endothelial receptor tyrosine kinase tie during the earliest stages of vascular development. The mouse tie cDNA was isolated and sequenced and the exon structure of the coding region was determined. The part of the tie gene encoding the extracellular domain was found to be organized in exons specifying the characteristic domains of the Tie polypeptide. Early postimplantation mouse tissues were analysed for tie expression by in situ hybridization. No tie mRNA was detected in 7.5 day mouse embryos. In 8.5 day embryos, tie expression was observed in differentiating angioblasts of the head mesenchyme, in the splanchnopleure and dorsal aorta as well as in migrating endothelial cells of the developing heart. A weak tie signal was also obtained from angioblasts in the blood islands of the yolk sac. Furthermore, tie mRNA was prominent in the endocardium of the embryo and in the endothelial cells forming the lung vasculature. Expression of tie persisted in the lung capillaries of adult mice, but was decreased in the endocardium. These results suggest that the tie receptor tyrosine kinase is involved in angiogenesis and/or maintenance of endothelial cell functions.
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PMID:The mouse tie receptor tyrosine kinase gene: expression during embryonic angiogenesis. 750 28

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is known to play a crucial role in mast cell growth and differentiation. In a human mast cell leukemia cell line (HMC-1), KitR was found to be constitutively phosphorylated on tyrosine, activated and associated with phosphatidylinositol 3-kinase (P13K) in the absence of autocrine production of SCF. Sequencing of c-kit cDNA revealed that c-kit genes of HMC-1 cells were composed of a normal, wild-type allele and a mutant allele with two point mutations in codon 560 and codon 816, resulting in intracellular amino acid substitutions of Gly-560 for Val and Val-816 for Asp, respectively. Murine c-kit mutants encoding Gly-559 and/or Val-814, corresponding to human Gly-560 and/or Val-816, were constructed by site-directed mutagenesis and expressed in cells of a human embryonic kidney cell line (293T). In the transfected cells, KitR (Gly-559 + Val-814) and KitR (Val-814) were strikingly phosphorylated on tyrosine and activated in the absence of SCF, whereas tyrosine phosphorylation and activation of KitR (Gly-559) or wild-type KitR was modest or little, respectively. These results suggest that constitutive activation of KitR in HMC-1 results from the activating mutations of c-kit gene, and raise the possibility that the activating mutations, particularly at codon 814 of murine c-kit or at codon 816 of human c-kit, may participate in oncogenesis of mast cells.
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PMID:Activating mutations of the c-kit proto-oncogene in a human mast cell leukemia cell line. 751 80

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is known to play a crucial role in hematopoiesis, especially in mast cell growth and differentiation. Although a number of dominant loss-of-function mutations of c-kit gene have been well characterized in mice, rats, and humans, little is known about the c-kit mutations contributing to ligand-independent activation of the c-kit receptor tyrosine kinase (KIT). In a murine mastocytoma cell line, P-815, KIT has been found to be constitutively phosphorylated on tyrosine and activated in a ligand-independent manner. Sequencing of the whole coding region of c-kit cDNA showed that c-kit cDNA of P-815 cells carries a point mutation in codon 814, resulting in amino acid substitution of Tyr for Asp. Murine wild-type c-kit cDNA and mutant-type c-kit cDNA encoding Tyr in codon 814 were expressed in cells of a human embryonic kidney cell line, 293T. In the transfected cells, mutant-form KITTyr814 was strikingly phosphorylated on tyrosine and activated in immune complex kinase reaction regardless of stimulation with a ligand for KIT (stem cell factor), whereas tyrosine phosphorylation and activation was barely detectable in wild-form KIT. The data presented here provide evidence for a novel activating mutation of c-kit gene that might be involved in neoplastic growth or oncogenesis of some cell types, including mast cells.
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PMID:Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation. 751 8

Constitutive overactivation of growth factor receptors through autocrine/paracrine mechanisms occurs frequently in cancer cells and are thought to play a critical role in carcinogenesis. In the present report, we propose a refined in vivo model which explains the significance of these mechanisms in tumour development. We have previously established transgenic mouse lines containing human papillomavirus type 16 (HPV16) E6E7 oncogenes, in male mice of which a Leydig cell tumor developes with a very high incidence. Not only HPV transgene but also the c-kit proto-oncogene receptor tyrosine kinase and its ligand Steel Factor (SLF) were coexpressed in all tumors analysed. This coexpression of c-kit/SLF was also found in two other Leydig cell tumor lines. Moreover, the proliferation of transgenic tumor cells was attenuated by treatment with a c-kit neutralizing antibody in vitro, strongly suggesting that tumorigenesis is closely related to stimulation of receptors through ligand induction. To confirm the significance of these findings, a defective mutation of the SLF gene in a laboratory mouse, the Steel-Dickey (Sld) mutation, was introduced into a line of transgenic mice showing 100% incidence of the tumor. In Sld-E6E7 transgenic mice, tumorigenesis was initiated but numbers of tumor cells were markedly reduced compared with transgenic mice carrying both wild type SLF allele, showing that c-kit activation through the induction of SLF is essential for testicular tumorigenesis, especially in tumour promotion. This transgenic mice system should be a useful in vivo model for clarifying the implication of growth factor autostimulation in carcinogenesis.
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PMID:An in vivo model for receptor tyrosine kinase autocrine/paracrine activation: auto-stimulated KIT receptor acts as a tumor promoting factor in papillomavirus-induced tumorigenesis. 753 Aug 26

Receptor tyrosine kinases play a central role in cellular growth, differentiation, and oncogenesis. All of these responses are triggered by growth factors interacting with the extracellular domain of transmembrane-spanning receptors, leading to dimerization and activation of an intrinsic tyrosine-specific kinase activity by an allosteric mechanism. Precise mechanisms of receptor dimerization remain poorly understood, and current models suggest that the ligand binding domain plays a major determining role. To examine the role of the intracellular domain in the association of juxtaposing receptor molecules, the full-length epidermal growth factor receptor was transiently co-expressed in human 293 fibroblasts with a truncated receptor that lacks the extracellular domain. After metabolic labeling with [35S]methionine, the association of these receptor constructs was monitored by co-immunoprecipitation with an extracellular domain-specific antibody. Specific interactions found between these receptors were independent of ligand binding or an intact ATP-binding site. Truncated receptors that had sequences necessary for membrane localization, and that were capable of interacting with full-length receptor tyrosine kinase, also displayed constitutive kinase activity as well as the capacity to transphosphorylate kinase-negative receptors. Receptor co-immunoprecipitation occurred between constructs that comprise the intracellular domains of the epidermal growth factor and beta-platelet-derived growth factor receptors, and HER-2. Subsequent deletion analysis has identified the major region of epidermal growth factor receptor intracellular interaction to be within the kinase domain.
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PMID:The kinase domain and membrane localization determine intracellular interactions between epidermal growth factor receptors. 753 98

The RET proto-oncogene encodes a protein receptor tyrosine kinase. RET mutations are associated with the dominantly inherited cancer syndromes multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma (FMTC). In MEN 2A, MEN 2B, and FMTC, direct detection of RET mutations can be used to identify disease allele carriers prior to the development of clinically evident neoplasms. RET mutations are also associated with sporadic thyroid carcinomas. The effects of RET mutation on protein function have been investigated both in vivo and in vitro, and the study of RET has served to provide insights into the mechanisms of tumorigenesis in general.
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PMID:RET gene and its implications for cancer. 756 85

Mutations in the receptor for the epidermal growth factor provide valuable insight into mechanisms of growth control. Oncogenic mutants of this receptor tyrosine kinase cause erythroid leukemia, fibrosarcoma, angiosarcoma, glioblastoma, and melanoma. Mutations in the avian protooncogene occur by retroviral mechanisms. Deletion of the ligand-binding domain results in erythroblastosis, while additional mutations in cytoplasmic structures broaden the disease potential to other cell types. A carboxyl-terminal structure of erbB oncogenes modulates growth responses in a complex, cell-specific manner; this tissue-specificity region appears to promote growth in erythroblasts and to produce trans-dominant inhibition in fibroblasts. Human glioblastoma multiforme frequently contains receptor mutations that are reminiscent of avian oncogenes. In hereditary melanoma of Xiphophorus, aberrant regulation of transcription by a recombinant promoter determines tissue-specific tumorigenesis. The diversity of oncogenic mutations raises important questions concerning the roles of several receptor structures. The extracellular domain inhibits the receptor when unoccupied by ligand, for example, through a mechanism that is unknown. The auto-phosphorylation sites are dispensable for transformation, so their function in neoplastic growth is unclear. The carboxyl-terminal region promotes or blocks transformation in different tissues, suggesting complex regulation by unknown cellular factors. These issues are critical to understanding of the mechanisms of receptor activation and tissue tropism for this family of oncogenes.
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PMID:Tissue-specific transformation by oncogenic mutants of epidermal growth factor receptor. 771 Nov 15


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