Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphatic vasculature has recently emerged as a prominent area in biomedical research because of its essential role in the maintenance of normal fluid homeostasis and the involvement in pathogenesis of several human diseases, such as solid tumor metastasis, inflammation and lymphedema. Identification of lymphatic endothelial specific markers and regulators, such as VEGFR-3, VEGF-C/D, PROX1, podoplanin, LYVE-1, ephrinB2 and FOXC2, and the development of mouse models have laid a foundation for our understanding of the major steps controlling growth and remodeling of lymphatic vessels. In this review we summarize recent advances in the field and discuss how this knowledge as well as use of model organisms, such as zebrafish and Xenopus, should allow further in depth analysis of the lymphatic vascular system.
Cell Mol Life Sci 2007 Aug
PMID:Molecular mechanisms of lymphatic vascular development. 1745 98

Glycan chains of asparagine-linked (N-linked) glycoproteins play a significant role in protein structure and function, as well as in angiogenesis an essential process for breast or other solid tumor growth. Non-availability of these chains causes incorrect folding of glycoproteins and leads to programmed cell death (i.e., apoptosis) through unfolded protein response (UPR) signaling. Cells actively processing cAMP signals modulate the glycan chain biosynthesis by PKA. Glycosylation of cellular proteins in a PKA type I-deficient CHO mutant 10248 was much reduced when compared with the wild type CHO 10001. The rate of LLO biosynthesis is similar in both cell types but quantitatively it is low in the mutant. Pulse-chase experiments indicated that the t(1/2) for LLO-turnover in CHO 10248 was twice as high as that of the wild type. This correlated with the reduced DPMS activity. The Km for GDP-mannose for the DPMS activity was 3-4 folds higher in the mutant than that of the wild type with or without exogenously added Dol-P. The kcat of DPMS was also reduced in the mutant. In vitro phosphorylation of microsomes from the CHO 10248 by PKA, on the other hand, restored the DPMS activity to the normal level. The LLO biosynthesis also improved significantly in MR1, a revertant of the CHO 10248. The turnover of LLO in MR1 and the glycoprotein profile were also at par with the wild type. Therefore, we conclude that PKA type I plays an important role in modulating the protein N-glycosylation in cAMP responsive cells.
Cell Mol Biol (Noisy-le-grand) 2007 May 15
PMID:Requirement of protein kinase type I for cAMP-mediated up-regulation of lipid-linked oligosaccharide for asparagine-linked protein glycosylation. 1753 Nov 50

The vascular endothelial growth factor-A (VEGF-A) signaling pathway, a key stimulant of solid tumor vascularization, is primarily dependent on the activation of the endothelial cell surface receptor VEGF receptor-2 (VEGFR-2). AZD2171 is an oral, highly potent small-molecule inhibitor of VEGFR tyrosine kinase activity that inhibits angiogenesis and the growth of human tumor xenografts in vivo. Here, we show pharmacodynamic changes in VEGFR-2 phosphorylation induced by AZD2171. In mouse lung tissue, a single dose of AZD2171 at 6 mg/kg inhibited VEGF-A-stimulated VEGFR-2 phosphorylation by 87% at 2 h with significant inhibition (>or=60%) maintained to 24 h. To examine inhibition of VEGFR-2 phosphorylation in tumor vasculature by immunohistochemistry, a comprehensive assessment of antibodies to various phosphorylation sites on the receptor was undertaken. Antibodies to the phosphotyrosine epitopes pY1175/1173 and pY1214/1212 were found suitable for this application. Calu-6 human lung tumor xenografts, from mice receiving AZD2171 or vehicle treatment (p.o., once daily), were examined by immunohistochemistry. A significant reduction in tumor vessel staining of phosphorylated VEGFR-2 (pVEGFR-2) was evident within 28 h of AZD2171 treatment (6 mg/kg). This effect preceded a significant reduction in tumor microvessel density, which was detectable following 52 h of AZD2171 treatment. These data show that AZD2171 is a potent inhibitor of VEGFR-2 activation in vivo and suggest that AZD2171 delivers therapeutic benefit in Calu-6 tumors by targeting vessels dependent on VEGFR-2 signaling for survival. In addition, this work highlights the utility of measuring either pY1175/1173 or pY1214/1212 on VEGFR-2 as a pharmacodynamic marker of VEGFR-2 activation.
Mol Cancer Ther 2007 Aug
PMID:Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts. 1769 17

(1) A new human glioblastoma multiforme (GBM) cell line, WJ1, was established from the tissue derived from a 29-year-old patient diagnosed with a grade IV GBM. (2) The WJ1 cell line has been subcultured for more than 80 passages in standard culture media without feeder layer or collagen coatings. (3) GBM cells grow in vitro with distinct morphological appearance. Ultrastructural examination revealed large irregular nuclei and pseudo-inclusion bodies in nuclei. The cytoplasm contained numerous immature organelles and a few glia filaments. Growth kinetic studies demonstrated an approximate population doubling time of 60 h and a colony forming efficiency of 4.04%. The karyotype of the cells was hyperdiploid, with a large subpopulation of polyploid cells. Drug sensitivities of DDP, VP-16, tanshinone IIA of this cell line were assayed. They showed a dose- and time-dependent growth inhibition effect on the cells. (4) Orthotopic transplantation of GBM cells into athymic nude mice induced the formation of solid tumor masses about 6 weeks. The cells obtained from mouse tumor masses when cultivated in vitro had the same morphology and ultrastructure as those of the initial cultures. (5) This cell line may provide a useful model in vitro and in vivo in the cellular and molecular studies as well as in testing novel therapies for human glioblastoma multiforme.
Cell Mol Neurobiol 2007 Nov
PMID:Establishment of a new human glioblastoma multiforme cell line (WJ1) and its partial characterization. 1770 57

The challenge of developing an atlas that catalogs all the functionally important genomic changes associated with the development of luminal-type breast cancer is discussed in this article. The development of genome-wide techniques such as expression profiling, array-based comparative genomic hybridization and unbiased sequencing have put a cancer genome atlas within reach. However these techniques have revealed that the somatic DNA alterations associated with the development of a common solid tumor such as breast cancer are extremely complex. For example, large scale tumor DNA resequencing projects, focused on a small number of cell lines and the analysis of many genes, suggest that as many as 100 somatic mutations may have accumulated by the time a diagnosis is made. Similarly, array comparative hybridization experiments have uncovered multiple gene amplification and deletion events. Dealing with this complexity requires access to tumor and matched normal DNA from a large number of cases, with sufficient material to complete a spectrum of analytical techniques. Second, an acceptable approach to patient consent or sample de-identification must be in place if DNA sequencing traces are to be entered into public databases. Third, samples must be linked to detailed information on disease outcomes in order to identify lesions associated with aggressive clinical behavior. We conclude that samples from neoadjuvant endocrine therapy clinical protocols offer the best sample sets to initiate a luminal breast cancer genome atlas because these studies are amongst the few in which investigators have obtained high quality frozen tumor samples associated with both short term information on the estrogen dependence of individual ER+ tumors, as well as conventional data on long-term cancer survival.
J Steroid Biochem Mol Biol
PMID:A luminal breast cancer genome atlas: progress and barriers. 1782 27

Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC(50) values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.
Mol Cancer Ther 2007 Sep
PMID:The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo. 1787 40

Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers. It is believed that tumor production of various immune suppressive mediators contributes to massively impaired immune functions, but the underlying signal transduction pathways are mostly unknown. Phosphorylation levels of MAP (mitogen-activated protein) kinase p38 were analyzed in permanent cell lines as well as in solid tumor tissue of HNSCC using flow cytometry and SDS-PAGE. Cytokine secretion was determined using the Cytometric Bead Array Flex Set system. MAP kinase p38 was shown to be activated in HNSCC by phorbol 12-myristate 13-acetate. Activation of p38 led to decreased cell proliferation and increased secretion of cytokines IL-6 and IL-8 in HNSCC. Our data provide novel insights into the origin of the HNSCC microenvironment. A better understanding of these molecular mechanisms in HNSCC is essential for novel drug development and improvement of the clinical perspective of this tumor type.
Int J Mol Med 2007 Dec
PMID:Increased cytokine secretion in head and neck cancer upon p38 mitogen-activated protein kinase activation. 1798 98

In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-d-glucose (2-DG) leads to cell death, whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-d-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/EBP-homologous protein), an unfolded protein response-specific mediator of apoptosis, more effectively in 2-DG-sensitive cells. We conclude that 2-DG seems to be toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor.
Mol Cancer Ther 2007 Nov
PMID:Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation. 1802 88

The ChemoFx Assay is an ex vivo assay designed to predict the sensitivity and resistance of a given patient's solid tumor to a variety of chemotherapy agents. A portion of a patient's solid tumor, as small as a core biopsy, is mechanically disaggregated and established in primary culture where malignant epithelial cells migrate out of tumor explants to form a monolayer. Cultures are verified as epithelial and exposed to increasing doses of selected chemotherapeutic agents. The number of live cells remaining post-treatment is enumerated microscopically using automated cell-counting software. The resultant cell counts in treated wells are compared with those in untreated control wells to generate a dose-response curve for each chemotherapeutic agent tested on a given patient specimen. Features of each dose-response curve are used to score a tumor's response to each ex vivo treatment as "responsive," "intermediate response," or "non-responsive." Collectively, these scores are used to assist an oncologist in making treatment decisions.
Methods Mol Biol 2008
PMID:The ChemoFx assay: an ex vivo chemosensitivity and resistance assay for predicting patient response to cancer chemotherapy. 1817 12

Proton beam is useful to target tumor tissue sparing normal cells by allowing precise dose only into tumor cells. However, the cellular and molecular mechanisms by which proton beam induces tumor cell death are still undefined. We irradiated three different tumor cells (LLC, HepG2, and Molt-4) with low energy proton beam (35 MeV) with spread out Bragg peak (SOBP) in vitro, and investigated cell death by MTT or CCK-8 assay at 24 h after irradiation. LLC and HepG2 cells were sensitive to proton beam at over 10 Gy to induce apoptosis whereas Molt-4 showed rather low sensitivity. Relative biological effectiveness (RBE) values for the death rate relative to gamma-ray were ranged from 1.1 to 2.3 in LLC and HepG2 but from 0.3 to 0.7 in Molt-4 at 11 d after irradiation by colony formation assay. The typical apoptotic nuclear DNA morphological pattern was observed by staining with 4'-6-diamidino-2-phenylindole (DAPI). Tiny fragmented DNA was observed in HepG2 but not in Molt-4 by the treatment of proton in apoptotic DNA fragment assay. By FACS analysis after stained with FITC-Annexin-V, early as well as median apoptotic fractions were clearly increased by proton treatment. Proton beam-irradiated tumor cells induced a cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) and procaspases-3 and -9. Activity of caspases was highly enhanced after proton beam irradiation. Reactive oxygen species (ROS) were significantly increased and N-acetyl cysteine pretreatment restored the apoptotic cell death induced by proton beam. Furthermore, p38 and JNK but not ERK were activated by proton and dominant negative mutants of p38 and JNK revived proton-induced apoptosis, suggesting that p38 and JNK pathway may be activated through ROS to activate apoptosis. In conclusion, our data clearly showed that single treatment of low energy proton beam with SOBP increased ROS and induced cell death of solid tumor cells (LLC and HepG2) in an apoptotic cell death program by the induction of caspases activities.
Exp Mol Med 2008 Feb 29
PMID:Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases. 1830 5


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