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)

Angiogenesis, the process of new vessels sprouting from the existing vasculature, is a critical process during early development. However, angiogenesis rarely occurs in the adult, except in response to cyclic hormonal stimulation in the ovary and uterus, in response to injury, and in response to pathological conditions such as tumorigenesis and diabetes mellitus. Tie2 (also known as Tek) is a novel endothelium-specific receptor tyrosine kinase, which has been demonstrated to be essential for the development of the embryonic vasculature; Tie2 knockout mice die by embryonic day 10.5 with specific defects in the formation of microvessels. Tie2 is downregulated later in embryogenesis, and its function in the adult has been relatively unexplored. To gain insight into the potential functions of Tie2 in the adult vasculature, Tie2 expression was examined in adult tissues undergoing angiogenesis and in quiescent tissues. Tie2 expression was localized by immunohistochemistry to the endothelium of neovessels in rat tissues undergoing angiogenesis during hormonally stimulated follicular maturation and uterine development and in healing skin wounds. Immunoprecipitation and RNase protection assay demonstrated upregulation of Tie2 protein and mRNA in rat and mouse skin wounds, respectively. Moreover, Tie2 immunoprecipitated from skin wounds was tyrosine-phosphorylated, indicating active downstream signaling. Surprisingly, Tie2 was also expressed in the entire spectrum of the quiescent vasculature (arteries, veins, and capillaries) in a wide range of adult tissues, and Tie2 immunoprecipitated from quiescent adult tissues was also tyrosine-phosphorylated. Together, these results suggest a dual function for Tie2 in adult tissues involving both angiogenesis and vascular maintenance.
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PMID:Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. 931 38

HER2/Neu is overexpressed in 25-30% of all human breast cancers as a result of both gene amplification and enhanced transcription. Transcriptional upregulation of HER2/neu leads to a 6-8-fold increased abundance of its mRNA per gene copy and likely results from the elevated activity of transcription factors acting on the HER2/neu promoter. Here we report that transcripts of PEA3, an ETS transcription factor implicated in oncogenesis, were increased in 93% of HER2/Neu-overexpressing human breast tumor samples. Analyses to uncover the molecular basis for elevated PEA3 transcripts in HER2/Neu-positive breast tumors revealed that the HER2/Neu receptor tyrosine kinase initiated an intracellular signaling cascade resulting in increased PEA3 transcriptional activity; transcriptionally-activated PEA3 stimulated HER2/neu and PEA3 gene transcription by binding to sites in the promoters of these genes. PEA3 also activates transcription of genes encoding matrix-degrading proteinases, enzymes required for tumor cell migration and invasion. These findings implicate PEA3 in the initiation and progression of HER2/Neu positive breast cancer, and suggest that PEA3 and signaling proteins affecting its regulation are appropriate therapeutic targets.
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PMID:HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer. 938 Apr 3

Protein tyrosine kinases (PTKs) play a role in regulating the growth and differentiated functions of thyroid cells and are probably involved in tumorigenesis of papillary-type thyroid carcinoma. To better understand the roles of PTKs in the physiology and pathophysiology of the thyroid, we analyzed the expression profile of receptor-type PTKs in normal human thyroid tissues. Highly conserved regions in the catalytic domains of receptor-type PTKs were amplified by RT-PCR using degenerate oligonucleotide primers. Nucleotide sequencing of about 100 clones identified 21 PTKs, including 16 receptor type and 5 nonreceptor type; no novel PTK was identified. Insulin-like growth factor I receptor, platelet-derived growth factor receptor (PDGFR), TrkE, Axl, epidermal growth factor receptor, etc., appear to be the most abundant receptor-type PTKs in the thyroid; many of which (PDGFR, TrkE, Axl, etc.) have never previously been demonstrated to be expressed in the thyroid. The expression of messenger RNAs (mRNAs) for PDGFR, axl, and trkE in normal thyroid cells was confirmed by Northern blot analysis, and interestingly, the expression levels of PDGFR and trkE mRNAs were decreased in all three thyroid carcinoma cell lines examined (FRO, WRO, and NPA), whereas axl mRNA and protein were overexpressed in 2 of 3 thyroid carcinoma cell lines (FRO and WRO) compared with that in normal tissue. The axl gene was, however, neither amplified nor rearranged. The biological activity of the ligand for Axl, the product of growth arrest-specific gene 6 (Gas6), was then evaluated, demonstrating modest mitogenic activity in thyroid carcinoma cells overexpressing Axl. Furthermore, gas6 mRNA was expressed in FRO cells. Thus, we here identify a variety of PTKs expressed in the thyroid gland, many of which may participate in the regulation of thyroid cell function. Variable expression levels of some PTKs in normal and cancerous cells suggest that there may be an imbalance and disarray of phosphorylation events in thyroid carcinoma cells. Furthermore, Gas6 is identified as a novel growth factor for thyroid carcinoma cells overexpressing Axl receptor tyrosine kinase.
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PMID:Expression profile of receptor-type protein tyrosine kinase genes in the human thyroid. 949 13

The (2;5)(p23;q35) lymphoma-associated chromosomal translocation creates a novel fusion gene that incorporates parts of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase and nucleophosmin genes. We report here that the product of this fusion gene accumulates within the nucleoli of neoplastic cells, and that previous reports of a predominantly cytoplasmic localization for the protein represent a tissue-processing artifact. However, nucleolar accumulation of nucleophosmin-ALK may not be necessary for its oncogenic action, because an ALK protein expressed in a lymphoma carrying a variant (1;2) chromosomal translocation did not accumulate in nucleoli. Furthermore, an engineered hybrid TPR-ALK protein can transform rodent fibroblasts and produce lymphomas in mice while remaining confined to the cytoplasm. We propose that the transforming action of ALK may not be reliant on its nucleolar localization, a hypothesis that may have implications for studies of other proteins involved in oncogenesis that are relocalized after the creation of fusion genes.
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PMID:Nucleolar localization of the nucleophosmin-anaplastic lymphoma kinase is not required for malignant transformation. 950 Apr 71

Inhibin-alpha subunit (Inh-alpha) gene expression is important for granulosa cell (GC) differentiation and prevention of ovarian tumorigenesis. Studies on Inh-alpha regulation have implicated activin and insulin-like growth factor-I (IGF-I) in the mechanisms of expression. Here we present evidence that endogenously produced IGF-I plays an obligatory role in activin-induced Inh-alpha production. Primary cultures of rat GC were incubated with increasing concentrations of various regulatory molecules, and the levels of Inh-alpha protein and its mRNA were measured in conditioned medium and cells, respectively. Recombinant activin A stimulated Inh-alpha expression, and the effects were dose- and time-dependent. The receptor tyrosine kinase inhibitor tyrphostin A23 caused a dose-dependent inhibition of activin-dependent Inh-alpha expression, whereas the inactive isomer, A63, had no effect. The stimulatory effect of activin was also blocked in a dose-dependent manner by added IGF binding protein-4 or -5, and the effects were reversed by IGF-I. Moreover, increasing concentrations of an anti-IGF-I antibody had a similar inhibitory effect on activin-stimulated Inh-alpha expression. Collectively, these results suggest, for the first time, that endogenously produced IGF-I is required for activin stimulation of Inh-alpha expression in cultured rat GC.
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PMID:Activin-induced inhibin alpha-subunit production by rat granulosa cells requires endogenous insulin-like growth factor-I. 951 Sep 58

The Lerks, ligands of eph-related receptor tyrosine kinases, are a rapidly expanding family of genes thought to play an important role in the development and oncogenesis of various tissues. However, very little experimental evidence supports this hypothesis. Using RNA fingerprinting, we detected increased expression of Lerk-5 mRNA in human melanocytes as a response to the tumor-promoting drug 12-O-tetradecanoylphorbol-13-acetate, which suggests a possible role of the Lerks in melanoma tumorigenesis and progression. Therefore, we studied Lerk-5 mRNA expression in various melanoma cell lines and tissues of melanocytic tumors by semiquantitative reverse transcription-PCR. Modest expression of Lerk-5 mRNA was found in two melanoma cell lines derived from early primary tumors (WM35 and WM1645B); two metastatic cell lines tested showed a 3.9-fold increased transcript abundance when compared to the primary cell lines (RPMI-7951 and SK-Mel5). Progeny of a melanoma cell line with very low Lerk-5 mRNA abundance (WM35) showed a 5-fold increase in Lerk-5 mRNA expression when it was selected for higher tumorigenicity and multicytokine resistance by passaging in nude mice or repeated high-dose UVB irradiation. Consistent with these experimental data, we found high levels of Lerk-5 mRNA expression in advanced primary malignant melanomas and metastases (n = 22) but significantly lower or undetectable mRNA expression in benign melanocytic nevi (n = 9; P < 0.001). We conclude that increased Lerk-5 expression possibly reflects or induces an increased potential of growth, tumorigenicity, and metastatic abilities in human melanomas. This makes the yet to be elucidated eph-related receptor tyrosine kinase/Lerk signaling system a potential new source for molecular markers as well as a target for new therapies.
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PMID:Overexpression of Lerk-5/Eplg5 messenger RNA: a novel marker for increased tumorigenicity and metastatic potential in human malignant melanomas. 953 49

RET is a receptor tyrosine kinase expressed in neuroendocrine cells and in tumors of these cell types. RET activation may be mediated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFR alpha-1). Activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia type 2 and in a subset of the related sporadic tumors, medullary thyroid carcinoma and pheochromocytoma, both being derived from neuroendocrine tissues. In one small study, mutations were identified in another tumor with neuroendocrine features, small cell lung carcinoma (SCLC). To determine whether RET mutations contribute to the pathogenesis of SCLC, we examined a panel of 54 SCLC cell lines. No mutations were identified in RET exons 10, 11, and 13-16, regions previously implicated in SCLC or other neuroendocrine tumors. We further examined the expression pattern of RET and the genes encoding the components of its ligand complex GDNF and GFR alpha-1, in 21 SCLC lines by using RT-PCR. Although we found no consistent pattern of expression for these three genes, RET was expressed in 57% of SCLC lines. Thus, although RET mutations appear unlikely to be an important step in the tumorigenesis of SCLC, the frequent expression of this gene suggests that RET may have a mitogenic role in a subset of SCLC cell lines.
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PMID:Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-I, in small cell lung carcinoma. 955 44

Receptor tyrosine kinases are key regulators of cellular function including cell growth, differentiation, migration, and morphogenesis. Disruptions of receptor tyrosine kinase signaling pathways are often associated with changes in cellular proliferative capacity and tumorigenesis. Both receptor-specific and cell type-specific factors may contribute to the ultimate cellular responses observed after receptor activation. In this regard, we find that both normal keratinocytes and their tumorigenic counterparts display differential responses to activation of receptor tyrosine kinases. Multiple ligands were mitogenic for keratinocytes, but only epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha), and scatter factor/hepatocyte growth factor (SF/HGF) promoted cell motility as assessed by colony dispersion (scattering) and in vitro reepithelialization. Interestingly, growth factor specificity for motility coincided with ligand-mediated cell invasion through a reconstituted basement membrane and induction of the 92-kDa metalloproteinase (MMP-9) activity as determined by gelatin zymogram analysis. Inhibitors of MMP activity or addition of an MMP-9 neutralizing antibody resulted in the loss of growth factor-induced colony dispersion, suggesting a functional role for MMP-9 induction during this response. Coordinate regulation of MMP-9 induction and the migratory response are likely to contribute to the enhanced invasive potential observed in response to EGF and SF/HGF. Our findings suggest that alternate receptor-mediated signaling pathways leading to differences in gene expression may be involved in complex cellular responses such as colony dispersion or invasion.
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PMID:Epidermal growth factor (EGF)- and scatter factor/hepatocyte growth factor (SF/HGF)- mediated keratinocyte migration is coincident with induction of matrix metalloproteinase (MMP)-9. 964 13

Neu (c-erbB2) is a proto-oncogene product that encodes an epidermal growth factor-like receptor tyrosine kinase. Amplification of wild-type c-Neu and mutational activation of Neu (Neu T) have been implicated in oncogenic transformation of cultured fibroblasts and mammary tumorigenesis in vivo. Here, we examine the relationship between Neu tyrosine kinase activity and caveolin-1 protein expression in vitro and in vivo. Recent studies have suggested that caveolins may function as negative regulators of signal transduction. Our current results show that mutational activation of c-Neu down-regulates caveolin-1 protein expression, but not caveolin-2, in cultured NIH 3T3 and Rat 1 cells. Conversely, recombinant overexpression of caveolin-1 blocks Neu-mediated signal transduction in vivo. These results suggest a reciprocal relationship between c-Neu tyrosine kinase activity and caveolin-1 protein expression. We next analyzed a variety of caveolin-1 deletion mutants to map this caveolin-1-dependent inhibitory activity to a given region of the caveolin-1 molecule. Results from this mutational analysis show that this functional in vivo inhibitory activity is contained within caveolin-1 residues 32-95. In accordance with these in vivo studies, a 20-amino acid peptide derived from this region (the caveolin-1 scaffolding domain) was sufficient to inhibit Neu autophosphorylation in an in vitro kinase assay. To further confirm or refute the relevance of our findings in vivo, we next examined the expression levels of caveolin-1 in mammary tumors derived from c-Neu transgenic mice. Our results indicate that dramatic reduction of caveolin-1 expression occurs in mammary tumors derived from c-Neu-expressing transgenic mice and other transgenic mice expressing downstream effectors of Neu-mediated signal transduction, such as Src and Ras. Taken together, our data suggest that a novel form of reciprocal negative regulation exists between c-Neu and caveolin-1.
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PMID:Reciprocal regulation of neu tyrosine kinase activity and caveolin-1 protein expression in vitro and in vivo. Implications for human breast cancer. 968 99

Specific germline mutations in the RET proto-oncogene predispose to the familial cancer syndromes: multiple endocrine neoplasia (MEN) types 2A and 2B, and familial medullary thyroid carcinoma. Expression of the RET receptor tyrosine kinase is tightly restricted to tumours of neural crest origin, such as neuroblastoma, and neuroblastoma has been observed in RET transgenic mice. Neuroblastoma tumour cell lines transfected with the MEN2A RET gene exhibit spontaneous neuritic differentiation, whereas MEN2B-type RET transfectants demonstrate altered cell adhesion and enhanced metastatic potential. In this study, the authors examined genomic DNA from 26 primary neuroblastoma tumours for MEN2A and MEN2B RET mutations, using restriction enzyme digestion of polymerase chain reaction products as an alternative to direct sequencing. Examination of RET exons 10 (codons 611, 618, 620), 11 (codons 632, 633, 634) and 16 (codon 918) in all 26 tumours revealed no RET mutations. Taken together these data suggest that abnormalities of the RET signalling pathway, rather than oncogenic, MEN2-type RET activation by mutation, may play a role in neuroblastoma tumorigenesis.
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PMID:Absence of MEN2A- or 2B-type RET mutations in primary neuroblastoma tumour tissue. 972 1


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