Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functional significance of phospholipase D (PLD) could most easily be investigated using selective inhibitors. We have isolated a family of fungal metabolites, ketoepoxides, that inhibit chemotactic peptide (formyl-Met-Leu-Phe)-stimulated PLD activation and superoxide generation in granulocytes in the low micromolar range (SCH 49210 having an IC50 of 1.6 microM). Unlike receptor-mediated PLD activation, ketoepoxides were poor inhibitors of phorbol ester-induced PLD activity in granulocytes (IC50 = 43 microM for SCH 49210). Ketoepoxides did not inhibit platelet-derived growth factor-stimulated PLD activity in fibroblasts at up to 50 microM. We also tested the effect of ketoepoxides on in vitro epidermal growth factor receptor and neu tyrosine kinase activities. SCH 49210 (and 49209) did not inhibit the tyrosine kinases at up to 100 microM. These results suggest that ketoepoxides do not inhibit PLD activation due to effects on tyrosine kinase activity. fMLP-induced phospholipase A2 (PLA2) activation is also inhibited by ketoepoxides in the low micromolar range (SCH 49210 having an IC50 of 3.2 microM), but the ketoepoxides were poorer inhibitors of Ca2+ ionophore A23187-induced PLA2 (SCH 49210 having an IC50 of 83 microM). As a measure of phospholipase C (PLC) activity, the generation of inositol-1,4,5 triphosphate in thrombin-stimulated platelets was measured. The ketoepoxides did not inhibit PLC activation indicating that, unlike the aminosteroid U73122, ketoepoxides exhibit some selectivity among receptor-linked phospholipases. The ketoepoxides were also effective inhibitors of tumor cell invasion, as measured by penetration of HT1080 human fibrosarcoma cells into a reconstituted basement membrane matrix. Interestingly, both PLD inhibition and anti-tumor invasion activity correlate closely. These ketoepoxides are, therefore, potential anti-metastatic compounds and may be useful probes to study the role of PLD in cell function.
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PMID:Novel ketoepoxides block phospholipase D activation and tumor cell invasion. 791 2

The her-2 (neu, erbB-2) oncogene encodes a 185-kDa transmembrane receptor tyrosine kinase. HER2 overexpression occurs in numerous primary human tumors and contributes to 25-30% of breast and ovarian carcinomas. Synthesis of HER2 is controlled in part by an upstream open reading frame (uORF) present in the transcript. We used synthetic capped and polyadenylated mRNAs containing sequences derived from the 5' region of the her-2 transcript fused to a firefly luciferase (LUC) reporter to examine this uORF's effect on translation in cell-free systems derived from reticulocytes, wheat germ and Neurospora crassa, and in RNA-transfected HeLa cells. The uORF reduced translation of the downstream cistron in all systems. [(35)S]Met labeling of in vitro translation products obtained indicated that the uORF also affected downstream start-site selection. Primer extension inhibition (toeprint) assays of ribosomes loaded at initiation codons in reticulocyte lysates indicated that the uORF affected the interaction of ribosomes with the primary her-2 AUG codon.
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PMID:her-2 upstream open reading frame effects on the use of downstream initiation codons. 1704 69

Geldanamycin (GA), a heat-shock protein (HSP) 90 inhibitor, induces degradation of HSP90 client proteins, which may promote the presentation of degradation peptides with major histocompatibility complex class I on cancer cells. We hypothesized that GA may enhance the efficacy of DNA vaccination, and investigated the therapeutic effect of the combination of GA and a DNA vaccine against HSP90 clients p185(neu) and Met. The efficacy of various doses of GA combined with an N-terminal neu (N'-neu) DNA vaccine was investigated in a transplanted tumor constitutively overexpressing endogenous p185(neu). Low-dose (2.5 mug) but not high-dose (10 microg) GA enhanced the effect of N'-neu DNA vaccination on the inhibition of murine bladder tumor-2 tumors in syngeneic C3H mice. Anti-p185(neu) antibody titers were similar among all treated groups. Significantly increased infiltrations of CD8(+) T cells and NK cells were observed at tumor sites. GA sensitized tumor cells to the cytotoxic effects of lymphocytes. Depletion of CD8(+) T cells eliminated most of the therapeutic efficacy; in contrast, depletion of CD4(+) T cells enhanced the therapeutic efficacy. A similar enhancing effect was observed for the combination of GA and a DNA vaccine targeting the Met oncogene. Our results support the use of combination of GA and DNA vaccination against GA-targeted proteins.
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PMID:Inhibitor of heat-shock protein 90 enhances the antitumor effect of DNA vaccine targeting clients of heat-shock protein. 1723 20