Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To characterize mechanisms which may determine the fate of apoptotic cells, we investigated chemokine expression in apoptotic promonocytic U937 cells or peripheral blood mononuclear cells (PBMC). Exposure of U937 cells to etoposide (VP-16) or the nitric oxide (NO) donor DETA-NO, both inducers of apoptosis in these cells, was associated with increased expression of the chemokines IL-8 and macrophage inflammatory protein-1 alpha. Up-regulation of IL-8 mRNA expression by VP-16 or DETA-NO was observed as early as 4 h or 6 h, respectively, after onset of treatment and was still detectable after 19 h of exposure. A serine protease inhibitor prevented both VP-16-induced apoptosis and release of IL-8, whereas inhibition of p38 MAP kinases reduced IL-8 secretion only. Moreover, we observed that incubation with 2-chlorodeoxyadenosine (CdA) up-regulated release of IL-8 from adherent PBMC in parallel to induction of apoptosis. In these cells a modest but significant induction of TNF-alpha release by CdA was also detected. In addition, CdA augmented release of IL-8 from whole blood cultures. By facilitating adequate recruitment of phagocytes to sites of cell death, stress-induced up-regulation of chemokines associated with apoptosis may contribute to mechanisms aiming at efficient removal of apoptotic cells.
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PMID:Expression and release of chemokines associated with apoptotic cell death in human promonocytic U937 cells and peripheral blood mononuclear cells. 1054 Mar 34

We examined early and late alterations in gene expression patterns and phosphorylation levels of key regulators of selected signaling pathways in U937 cells exposed to various (*)NO fluxes. cDNA microarray analysis and real-time quantitative PCR identified 45 NO-sensitive genes (>or=2-fold change), among which KLF2, KLF6, TSC22D3, DDIT4, MKP-5 (up-regulated), KIF23, histone H4, ARL6IP2, CLNS1A, SLC7A6, CDKN3, SRP19, and BCL11A (down-regulated) have not been reported before. For two selected genes, KLF2 and DDIT4, the sensitivity to (.)NO was also proven at the protein level. Among the examined genes, only KLF2 had a higher sensitivity to slow release of NO (DETA-NO) than to high-dose, short-duration exposure (DPTA-NO), reaching an about 50-fold increase in mRNA level. Our study revealed that fast and slow NO donors activate similar signaling pathways and induce phosphorylation of MAP kinases and downstream transcription factors ATF2 and c-Jun. Inhibitory analysis of major signaling pathways showed that activity of p38 MAPK and tyrosine kinases is indispensable for gene induction in cells exposed to DPTA-NO, whereas G-protein Rho suppression caused superinduction of KLF2 in (*)NO-stimulated cells. Finally, we showed that both (*)NO donors caused a marked decrease in phosphorylation of p70S6K, an mTOR substrate and regulator of mRNA translation, and protein kinase Akt, an upstream positive regulator of mTOR.
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PMID:Variation in gene expression profiles of human monocytic U937 cells exposed to various fluxes of nitric oxide. 1989 11

Vitamin D signaling in mammary cancer stem cells (MCSCs), which are implicated in the initiation and progression of breast cancer, is poorly understood. In this study, we examined vitamin D signaling in mammospheres which are enriched in MCSCs from established breast cancer cell lines. Breast cancer cells positive for aldehyde dehydrogenase (ALDH(+)) had increased ability to form mammospheres compared to ALDH(-) cells. These mammospheres expressed MCSC-specific markers and generated transplantable xenografts in nude mice. Vitamin D receptor (VDR) was significantly down-regulated in mammospheres, as well as in ALDH(+) breast cancer cells. TN aggressive human breast tumors as well as transplantable xenografts obtained from SKBR3 expressed significantly lower levels of VDR but higher levels of CD44 expression. Snail was up-regulated in mammospheres isolated from breast cancer cells. Inhibition of VDR expression by siRNA led to a significant change in key EMT-specific transcription factors and increased the ability of these cells to form mammospheres. On the other hand, over-expression of VDR led to a down-regulation of Snail but increased expression of E-cad and significantly compromised the ability of cells to form mammospheres. Mammospheres were relatively insensitive to treatment with 1,25-dihydroxyvitamin D (1,25D), the active form of vitamin D, compared to more differentiated cancer cells grown in presence of serum. Treatment of H-Ras transformed HMLE(HRas) cells with DETA NONOate, a nitric oxide (NO)-donor led to induction of MAP-kinase phosphatase -1 (MKP-1) and dephosphorylation of ERK1/2 in the mammospheres. Combined treatment of these cells with 1,25D and a low-concentration of DETA NONOate led to a significant decrease in the overall size of mammospheres and reduced tumor volume in nude mice. Our findings therefore, suggest that combination therapy using 1,25D with drugs specifically targeting key survival pathways in MCSCs warrant testing in prospective clinical trial for treatment of aggressive breast cancer.
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PMID:Down-regulation of vitamin D receptor in mammospheres: implications for vitamin D resistance in breast cancer and potential for combination therapy. 2334 35