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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have established the human nck sequence as a new oncogene. Nck encodes one SH2 and three SH3 domains, the Src homology motifs found in nonreceptor tyrosine kinases, Ras GTPase-activating protein, phosphatidylinositol 3-kinase, and phospholipase C-gamma. Overexpression of human nck in 3Y1 rat fibroblasts results in transformation as judged by alteration of cell morphology, colony formation in soft agar, and tumor formation in nude BALB/c mice. However, overexpression of nck does not induce detectable elevation of the phosphotyrosine content of specific proteins, as is observed for v-crk, another SH2/SH3-containing oncogene. Despite this fact, we demonstrate that Nck retains the ability to bind tyrosine phosphorylated proteins in vitro, using a fusion protein of Nck with glutathione-S-transferase (GST). Moreover, when incubated with lysates prepared from v-src-transformed 3Y1 cells or the nck-overexpressing cell lines, GST-Nck binds to both p60v-src and serine/threonine kinases, respectively. Although phosphotyrosine levels are not elevated in the nck-expressing fibroblasts, vanadate treatment of these cells results in a phosphotyrosine pattern that is altered from the parental 3Y1 pattern, suggestive of a perturbation of indigenous tyrosine kinase pathways. These results suggest the possibility that human nck induces transformation in 3Y1 fibroblasts by virtue of its altered affinity or specificity for the normal substrates of its rat homolog and that Nck may play a role in linking tyrosine and serine/threonine kinase pathways within the cell.
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PMID:The SH2- and SH3-containing Nck protein transforms mammalian fibroblasts in the absence of elevated phosphotyrosine levels. 128 Mar 26

Growth factor receptors are important determinants of both normal and abnormal cell growth. We have now used degenerate primers designed from conserved tyrosine kinase domains to identify and clone a novel receptor-like molecule (designated Nbtk-1) from a NB41 mouse neuroblastoma cell line. Nbtk-1 is related to the met proto-oncogene family of tyrosine kinase receptors. Transcripts of approximately 2.1 and 2.6 kb have been found in mouse cell lines and one transcript of approximately 3 kb in human cell lines and in a wide range of primary human tumors, such as neuroblastomas, primitive neuroectodermal tumors (PNETs), Wilms' tumors, and melanomas and in the corresponding normal human tissues. These observations suggest that Nbtk-1 may have important roles in normal and tumor cell growth.
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PMID:Identification of a novel tyrosine kinase receptor-like molecule in neuroblastomas. 128 89

The epidermal growth factor receptor gene is the most frequently involved proto-oncogene in human glial brain tumors, in the present series in agreement with previous reports in literature. It is therefore important to study this gene from DNA to the protein product. The vicinity of cystic fluid (C.F.) to tumor cells of the cystic wall has suggested investigation of possible "E.G.F.-like" autocrine activities in C.F. In 40% of gliomas, E.G.F.-R. gene is amplified and overexpressed. This is never observed in low grade astrocytomas. In 12% of the cases, mutations of the E.G.F.-R. gene are observed. In correlation with genomic abnormalities, E.G.F.-R. is immunoprecipitated in 40% gliomas. The basal phosphorylation of the receptor is increased in 50% gliomas. In C.F., unexpectedly, E.G.F.-R. phosphorylation inhibitory effect is observed. Its biochemical analysis suggests an anti-tyrosine kinase activity. The observation of anti-tyrosine kinase activity in C.Fs suggests the presence of negative modulatory factors of the proto-oncogene activation in tumor tissues. This could have therapeutical interest.
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PMID:[The EGF receptor pathway in human cerebral tumors]. 129 71

Chronic myelogenous leukaemia is a clonal neoplasm of the pluripotent haematopoietic stem cell which is characterized in most patients by a consistent cytogenetic abnormality known as the Philadelphia chromosome. This chromosome occurs as a consequence of a reciprocal translocation between the long arms of chromosomes 9 and 22 which results in the creation of a new gene comprising sequences from the c-abl gene on chromosome 9 and the bcr gene on chromosome 22. The protein encoded by this structurally altered hybrid gene differs from the normal c-abl gene product in both molecular weight and in tyrosine kinase activity. It is likely that these alterations in the c-abl gene product play a central role in the pathogenesis of this leukaemia.
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PMID:Molecular pathogenesis of chronic myelogenous leukaemia. 130 82

The MCF-7 cell line is a hormone-responsive human breast-cancer cell line, which has been extensively used in studies of estrogen regulation of cell growth. These studies have indicated that the growth stimulation of the MCF-7 cells by estrogens may be effected by an autocrine mechanism involving several growth factors, such as EGF, TGF alpha and IGF-I and their receptors. We have amplified and cloned tyrosine-kinase-related sequences from the MCF-7 cell mRNA using the polymerase chain reaction and characterized the partial cDNAs obtained by nucleic acid sequencing. Nine tyrosine kinase cDNAs and one serine/threonine kinase cDNA were identified among the amplified sequences. Four different tyrosine kinase genes encoding receptors for fibroblast growth factors (FGFs) were found to be expressed by the MCF-7 cells. In addition, differences were observed in the expression of these members of FGF receptor family in different breast-cancer cells. A putative tyrosine-kinase receptor and a novel serine/threonine kinase were preferentially expressed in estrogen-responsive tumor cell lines. However, no estrogen-dependent regulation of any of the novel tyrosine-kinase receptor mRNAs was found in any of the cell lines including the MCF-7 or ZR-75-I cells, where the expression of the neu proto-oncogene mRNA was decreased during estrogen treatment. The expression of several FGF receptors by breast-cancer cells suggests that FGFs may be involved in their growth regulation and tumorigenesis.
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PMID:Analysis of tyrosine kinase mRNAs including four FGF receptor mRNAs expressed in MCF-7 breast-cancer cells. 131 Dec 87

We describe the molecular cloning of a receptor tyrosine kinase from a cell line (LK63) derived from a case of human pre-B-cell leukemia. We have previously shown that a monoclonal antibody (IIIA4) raised against LK63 recognized a glycosylated, cell-surface 135-kDa molecule (HEK), which displayed tyrosine kinase activity in vitro. The HEK protein was purified by using a IIIA4 antibody column and both N-terminal and internal amino acid sequences were obtained. A 51-mer degenerate oligonucleotide based on the internal amino acid sequence was used to screen an LK63-derived lambda gt10 cDNA library under low-stringency hybridization conditions. One clone of 2.5 kilobases (kb) was isolated and characterized and used to rescreen the library under more-stringent hybridization conditions. A 4.5-kb clone containing the entire HEK coding region was isolated and its complete DNA sequence was determined. The 4.5-kb insert was subcloned into the expression vector CDM8 and transfected into COS cells. COS cells transfected with the sense HEK/CDM8 construct stained specifically with the IIIA4 antibody, thereby confirming that the antigen recognized by the IIIA4 antibody and the expressed protein product of the HEK cDNA clone were identical. DNA sequence analysis revealed that HEK is a newly discovered member of the EPH/ELK family of receptor tyrosine kinases. Northern blot analysis of a number of cell lines demonstrated the expression of 5.5- to 6.0-kb HEK transcripts in LK63 and the T-cell lines JM and HSB-2. Southern blot analysis of DNA from LK63 suggested that the HEK gene was neither amplified nor rearranged in the LK63 tumor.
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PMID:Molecular cloning of HEK, the gene encoding a receptor tyrosine kinase expressed by human lymphoid tumor cell lines. 131 45

Hepatocyte growth factor (HGF) is the most potent mitogen for mature hepatocytes and seems to act as a hepatotropic factor that has not been purified over the past 30 years. HGF was first purified from rat platelets in 1986. HGF is a hetrodimer molecule composed of 69-kDa alpha-subunit and 34-beta-subunit. In 1989, cDNAs of both human and rat HGF were cloned and primary structure of HGF was determined. HGF is derived from preproprecursor of of 728 amino acids, which is proteolytically processed to form mature HGF. The alpha-chain contains four kringle domains and it has 38% homology with plasmin. HGF mRNA and HGF activity increase markedly in the liver of rats after various liver injuries such as hepatitis, ischemia, physical crush, and partial hepatectomy. Production of HGF in the liver occurs in Kupffer cells and sinusoidal endothelial cells, but not in parenchymal hepatocytes. HGF mRNA is also markedly increased even in the intact lung, kidney, and spleen after injuries of the liver. Therefore, HGF may act as a trigger for liver regeneration through two mechanisms: a paracrine mechanism and an endocrine mechanism. Moreover, HGF mRNA increases markedly in the kidney after various renal injuries, thus it suggests that HGF may act not only as a hepatotropic factor but also as a renotropic factor. HGF receptor with a Kd of 20 to 30 pM is widely distributed in various epithelial cells including hepatocytes. HGF receptor was recently identified as the product of c-met protooncogene, which encodes a 190-kDa transmembrane protein possessing tyrosine kinase domain. HGF has recently been shown to be a pleiotropic factor. HGF stimulates growth of various epithelial cells, including renal tubular cells (Mitogen). It is worth noting that HGF strongly enhances motility of epithelial cells (Motogen) and induces epithelial tubule formation (Morphogen), while it strongly inhibits growth of several tumor cells. All these findings indicate that HGF may have important roles in organogenesis, morphogenesis, carcinogenesis, as well as in organ regeneration.
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PMID:Hepatocyte growth factor: molecular structure, roles in liver regeneration, and other biological functions. 131 69

High- and low-metastatic cells derived from metastatic murine tumors were screened for the differential expression of proto-oncogenes which may code for cell-surface receptors to growth factors. We found that metastatic clones of 3LL carcinoma and T10 sarcoma but not non-metastatic clones of these tumors express a 6.5-kb mRNA that is recognized by a v-fms probe containing a tyrosine kinase domain. The cloning and sequence analysis of a full-length cDNA clone corresponding to the v-fms-related 6.5-kb transcript showed that this transcript is the murine homolog of platelet-derived growth factor alpha (PDGF-alpha) receptor. The cDNA contains an open reading frame that predicts a 1089 amino acid protein. Comparison with the human and rat PDGF-alpha receptor reveals an overall amino acid sequence identity of 91% and 94% respectively. Northern blot analysis shows that this gene is preferentially expressed in the high-metastatic clones and is also selectively expressed in normal mouse tissues. Immunoprecipitation using anti-PDGF-alpha receptor serum shows that 185-kDa and 170-kDa proteins were specifically precipitated from cells of the high-metastatic D122 but not from the low-metastatic A9 cells. The possibility that overexpression of PDGF-alpha receptor in high-metastatic clones may contribute to an increase in the capacity of tumor cells to generate metastases in the lung is discussed.
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PMID:Mouse platelet-derived growth factor alpha receptor: sequence, tissue-specific expression and correlation with metastatic phenotype. 132 4

Oncostatin M is a polypeptide cytokine produced by activated and transformed T lymphocytes that has diverse biologic effects, including growth inhibition of tumor cells and induction of IL-6 expression in cultured human endothelial cells (HEC). HEC are highly responsive to oncostatin M and express high levels of oncostatin M receptors relative to other cell types. Oncostatin M has previously been found to bind a specific receptor of 150 to 160 kDa. We have found through the use of anti-phosphotyrosine immunoblotting that oncostatin M induces tyrosine phosphorylation in HEC. Anti-phosphotyrosine antibodies specifically immunoprecipitated labeled oncostatin M cross-linked to its receptor, demonstrating that the oncostatin M receptor is either directly phosphorylated on tyrosine after ligand binding or is tightly associated with a phosphotyrosyl protein in these cells. The tyrosine kinase inhibitor herbimycin A blocked the induction of IL-6 by oncostatin M in HEC. In addition, immune complex kinase assays showed that oncostatin M markedly increased the activity of the p62yes tyrosine kinase with a small increase in p59fyn but no increase in p56lyn tyrosine kinase activity in HEC. We conclude that oncostatin M utilizes a tyrosine phosphorylation signal transduction pathway in HEC involving the activation of the p62yes tyrosine kinase, and that this tyrosine phosphorylation pathway leads to the induction of IL-6 expression.
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PMID:Oncostatin M induces tyrosine phosphorylation in endothelial cells and activation of p62yes tyrosine kinase. 132 79

A gene transfer model was developed which allows for the identification of transformation pathways in the developing nervous system. Transforming genes were introduced into fetal brain transplants using embryonic CNS as donor tissue and replication-defective retroviral vectors as genetic vehicles. This technique relies on the extraordinary organotypic differentiation capacity of neural grafts and the expression of retrovirally transmitted genes in various cell types of CNS transplants. In contrast to transgenic animals but analogous to sporadic tumor formation, target cells for the retroviral vector develop in an environment of unmodified neural tissue. We have introduced a number of neurotropic oncogenes into fetal brain transplants including genes with an associated tyrosine kinase activity (polyoma medium T, v-src), a novel member of the fibroblast growth factor (fgf) gene family and the SV40 large T antigen. These experiments have demonstrated a significant transformation potential of oncogenes in specific target cells of the brain, provided evidence for a dominant complementary transforming effect of simultaneously expressed ras and myc genes in neural precursor cells and have yielded intriguing model systems for human CNS neoplasms such as the cerebellar medulloblastoma. This review describes the transplantation model, demonstrates several striking phenotypes induced by oncogene expression in neural grafts and elaborates on future prospects of this experimental approach.
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PMID:Retrovirus-mediated oncogene transfer into neural transplants. 134 47


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