Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that sodium arsenite downregulates NF-kappaB activity by inhibiting phosphorylation and subsequent degradation of IkappaBalpha. Many effects of sodium arsenite are secondary to induction of heat shock proteins. The role of the heat shock response in arsenite-induced inhibition of NF-kappaB, however, is not known. We examined the involvement of the heat shock response in arsenite-induced inhibition of NF-kappaB activity in IL-1beta-stimulated Caco-2 cells, a human colorectal adenocarcinoma cell line with enterocytic properties. Treatment of the cells with IL-1beta resulted in increased IkappaB kinase activity, reduced levels of IkappaBalpha and increased NF-kappaB DNA binding activity. Sodium arsenite blocked all of these responses to IL-1beta without inducing changes in heat shock factor activity or heat shock protein levels. Results from additional experiments showed that the protective effect of sodium arsenite on IkappaBalpha was not influenced by the oxygen radical scavenger catalase or by inhibitors of the MAP-kinase signaling pathway. The present results suggest that sodium arsenite stabilizes IkappaBalpha and prevents NF-kappaB activation in IL-1beta-stimulated Caco-2 cells independent of the heat shock response. In addition, stabilization of IkappaBalpha by sodium arsenite does not require oxygen radical formation or activation of the MAP kinase signaling pathway.
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PMID:Arsenite stabilizes IkappaBalpha and prevents NF-kappaB activation in IL-1 beta-stimulated Caco-2 cells independent of the heat shock response. 1183 94

We investigated the potential of genistein, the primary isoflavone of soy, to protect against breast and prostate cancers in animal models. For mammary cancer studies, Sprague-Dawley rats were fed AIN-76A diet plus minus 250 mg genistein/kg diet. Dimethylbenz[a]anthracene was administered by gavage at d 50 postpartum to induce mammary tumors. Mammary cancer chemoprevention was demonstrated after prepubertal and combined prepubertal and adult genistein treatments but not after prenatal- or adult-only treatments, demonstrating that the timing of exposure to genistein is important for mammary cancer chemoprevention. The cellular mechanism of action was found to be mammary gland and cell differentiation, as shown by whole-mount analysis and beta-casein expression. An imprinting effect was shown for epidermal growth factor receptor expression in mammary terminal end buds. For prostate cancer studies, we used two models. The first was a chemically (N-methylnitrosourea) induced prostate cancer rat model. Genistein in the diet inhibited the development of invasive adenocarcinomas in a dose-dependent manner. The second model was a transgenic mouse model that resulted in spontaneously developing adenocarcinoma tumor of the prostate. Genistein in the diet reduced the incidence of poorly differentiated prostatic adenocarcinomas in a dose-dependent manner and down-regulated androgen receptor, estrogen receptor-alpha, progesterone receptor, epidermal growth factor receptor, insulin-like growth factor-I, and extracellular signal-regulated kinase-1 but not estrogen receptor-beta and transforming growth factor-alpha mRNA expressions. We conclude that dietary genistein protects against mammary and prostate cancers by regulating specific sex steroid receptors and growth factor signaling pathways.
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PMID:Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. 1188 May 92

Laminin-5 is an extracellular matrix protein that plays a key role in cell migration and tumor invasion. Cox-2 is an induced isoform of cyclooxygenases that plays an important role in carcinogenesis, suppression of apoptosis, angiogenesis, and metastasis of colon cancer. We report frequent co-expression of cox-2 and laminin-5 at the invasive front of early-stage lung adenocarcinomas. We investigated the expression of cox-2 and laminin-5 immunohistochemically in 102 cases of small-sized lung adenocarcinoma (maximum dimension, 2 cm or less). Cox-2 and laminin-5 were expressed in 97 (95.1%) and 82 (80.4%) cases, respectively. Both were preferentially localized in cancer cells at the cancer-stroma interface, although cox-2 tended to show a diffuse staining pattern in some cases. A comparison of their staining patterns revealed a striking similarity in their distribution in 24 cases, and a partial overlap between their localization in another 20 cases. Moreover, an overall correlation was found between the expression levels of cox-2 and laminin-5 (P = 0.018). To gain insight into the mechanisms that regulate the expression of these proteins, we additionally studied their expression in 58 cases of stage I lung adenocarcinoma, in which p53 status was determined by immunohistochemistry, polymerase chain reaction-single strand conformation polymorphism analysis, and direct sequencing. The results showed that tumors with mutant p53 tended to express more cox-2 than those with wild-type p53 (P = 0.080). Also, tumors that overexpressed p53 had higher levels of cox-2 and laminin-5 than those without p53 overexpression (P = 0.032 and 0.047, respectively). Further immunohistochemical analysis showed that tumors that overexpressed both epidermal growth factor receptor (EGFR) and erbB-2 had higher levels of cox-2 and laminin-5 than those without concomitant overexpression of these proteins (P = 0.014 and P = 0.018, respectively). To see whether EGFR signaling is involved in cox-2 and laminin-5 expression, we further conducted in vitro analyses using six lung adenocarcinoma cell lines (A549, HLC-1, ABC-1, LC-2/ad, VMRC-LCD, and L27). Western blot analyses showed that cox-2 mRNA levels, and to a lesser extent laminin-5 gamma2 mRNA levels, correlated with the expression levels of erbB-2 and the phosphorylated form of MAPK/ERK-1/2 protein. The addition of transforming growth factor-alpha increased both cox-2 and laminin-5 gamma2 mRNA levels in A549, ABC-1, and L27 with different kinetics; the induction of cox-2 occurred earlier than that of laminin-5 gamma2. Finally, the migration of ABC-1 cells was inhibited by MAP kinase kinase inhibitor PD98059 and a selective cox-2 inhibitor NS-398. In contrast, the migration of A549 cells was inhibited by PD98059, but much less effectively by NS-398. These results suggest that co-stimulatory mechanisms may exist that increase the expression of cox-2 and laminin-5 at the invasive front of lung adenocarcinomas and that EGFR signaling could be one of the mechanisms. Further investigations are warranted concerning the role of cox-2 and laminin-5 in cancer cell invasion and the significance of p53 and EGFR signaling in the regulation of cox-2 and laminin-5 expression.
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PMID:Frequent co-localization of Cox-2 and laminin-5 gamma2 chain at the invasive front of early-stage lung adenocarcinomas. 1189 Dec 9

Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling and oncogenesis. Caveolin-1 is down-regulated in oncogene-transformed and tumor-derived cells. Antisense suppression of caveolin-1 or expression of a dominant negative form are sufficient for inducing cellular transformation. Expression of recombinant caveolin-1 inhibits anchorage-independent growth in cancer cells. The present study was designed to determine whether this is caused by inhibition of cancer cell survival or cell proliferation, and to test if another important property of cancer cells, i.e. matrix invasion, is modulated by expression of caveolin. Utilizing MCF-7 human breast adenocarcinoma cells stably transfected with caveolin-1 (MCF-7/Cav1), we demonstrate that caveolin-1 expression decreases MCF-7 cell proliferation rate and markedly reduces their capacity to form colonies in soft agar. The loss of anchorage-independent growth is not associated with stimulation of anoikis; in fact, MCF-7/Cav1 cells exhibit increased survival after detachment as compared with MCF-7 cells, indicating that in these cells caveolin-1 inhibits anoikis. Analysis of matrix metalloprotease release and matrix invasion revealed that expression of caveolin-1 inhibits also these important metastasis-related phenomena. Plating MCF-7 cells on a laminin matrix resulted in activation of ERK1/2, which was dramatically inhibited in MCF-7/Cav1 cells. We conclude that high expression level of caveolin-1 in human breast cancer cells exerts a negative modulatory effect on anchorage-independent growth by inhibiting cell proliferation even though matrix-independent cell survival is enhanced. Caveolin-1 expression inhibits also matrix invasion and blocks laminin-dependent activation of ERK1/2. The inhibitory effect of caveolin-1 on these transformation-dependent processes supports the hypothesis that caveolin-1 acts as a tumor suppressor protein which may impose major phenotypic changes when expressed in human cancer cells.
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PMID:Caveolin-1 inhibits anchorage-independent growth, anoikis and invasiveness in MCF-7 human breast cancer cells. 1194 20

The H19 gene is an imprinted gene expressed from the maternal allele. It is known to function as an RNA molecule. We previously reported that in breast adenocarcinoma, H19 is often overexpressed in stromal cells and preferentially located at the epithelium/stroma boundary, suggesting that epithelial/mesenchymal interactions can control H19 RNA expression. In some cases of breast adenocarcinoma with poor prognosis, H19 is overexpressed in epithelial cells. Therefore we examined whether mesenchymal factors can induce H19 expression in epithelial cells. Using quantitative RT-PCR and in situ hybridization, we found that when mammary epithelial cells were cultured in collagen gels, H19 expression was strongly up-regulated compared to when cells were cultured on plastic. Collagen gels allow three-dimensional growth of epithelial cells and morphogenetic responses to soluble factors. A conditioned medium from MRC-5 fibroblasts caused branching morphogenesis of HBL-100 cells and invasive growth of MDA-MB-231 cells, whereas MCF-7 cells were unresponsive. Induction of H19 expression correlated with morphological changes in HBL-100 and in MDA-MB-231 cells, whereas H19 expression was not induced in MCF-7 cells. Using a blocking antibody, HGF/SF was identified as the fibroblast-derived growth factor capable of inducing H19 expression and cell morphogenesis. We further demonstrated that H19 promoter activity was stimulated by various growth factors using transient transfection in MDCK epithelial cells. HGF/SF was more efficient than EGF or FGF-2 in transactivating the H19 promoter, whereas IGF-2, TGFbeta-1, and TNF-alpha were ineffective. This activation by HGF/SF was prevented by pharmacological inhibition of MAP kinase or of phospholipase C. We conclude that H19 is a target gene for HGF/SF, a known regulator of epithelial/mesenchymal interactions, and suggest that the up-regulation of H19 may be implicated in morphogenesis and/or migration of epithelial cells.
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PMID:Cross-talk between mesenchyme and epithelium increases H19 gene expression during scattering and morphogenesis of epithelial cells. 1196 91

MUC2 is a secretory mucin normally expressed by goblet cells of the intestinal epithelium. It is overexpressed in mucinous type colorectal cancers but down-regulated in colorectal adenocarcinoma. Phorbol 12-myristate 13-acetate (PMA) treatment of colon cancer cell lines increases MUC2 expression, so we have undertaken a detailed analysis of the effects of PMA on the promoter activity of the 5'-flanking region of the MUC2 gene using stably and transiently transfected promoter reporter vectors. Protein kinase C inhibitors (bisindolylmaleimide, calphostin C) and inhibitors of mitogen-activated protein/extracellular signal regulated kinase kinase (MEK) (PD98059 and U0126) suppressed up-regulation of MUC2. Src tyrosine kinase inhibitor PP2, a protein kinase A inhibitor (KT5720), and a p38 inhibitor (SB 203580) did not affect transcription. Western blotting and reverse transcription-PCR analysis confirmed these results. In addition, co-transfections with mutants of Ras, Raf, and MEK showed that the induction of MUC2 promoter activity by PMA required these three signaling proteins. Our results demonstrate that PMA activates protein kinase C, stimulating MAP kinase through a Ras- and Raf-dependent mechanism. An important role for nuclear factor kappaB (NF-kappaB) was also demonstrated using the inhibitor caffeic acid phenethyl ester and electrophoretic mobility shift assays. Such identification of pathways involved in MUC2 up-regulation by PMA in the HM3 colon cancer cell line may serve as a model for the effects of cytokines and growth factors, which regulate MUC2 expression during the progression of colorectal cancer.
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PMID:Phorbol 12-myristate 13-acetate up-regulates the transcription of MUC2 intestinal mucin via Ras, ERK, and NF-kappa B. 1207 18

Neurotensin (NT) is a neuropeptide interacting with specific G protein coupled receptors. In the periphery, NT is a hormone of the gastrointestinal tract. The high affinity neurotensin receptor (NT-1 receptor) is over-expressed in a numbers of cancers. Consequently NT growth effects, largely described in normal and adenocarcinomatous tissues, may be of a major importance in tumor proliferation. In this study we demonstrated an anti-apoptotic effect of NT agonist, in the mammary adenocarcinoma cells, MCF-7. Focusing on the cellular events involved, we found an increase in Bcl-2 protein and mRNA levels, resulting in Bcl-2 transcriptional activation, and dependent on MAP kinase pathway.
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PMID:Neurotensin counteracts apoptosis in breast cancer cells. 1215 Sep 75

Over the past few years, we have shown that the surge of melatonin in the circulation during darkness represents a potent oncostatic signal to tissue-isolated rat hepatoma 7288CTC, which is an ER+ adenocarcinoma of the liver. This oncostatic effect occurs via a melatonin receptor-mediated suppression of tumor cAMP production that leads to a suppression of the tumor uptake of linoleic acid (LA), an essential fatty acid with substantial oncogenic properties. The ability of LA to promote cancer progression is accomplished by its intracellular metabolism to 13-hydroxyoctadecadienoic acid (13-HODE) which amplifies the activity of the epidermal growth factor receptor/mitogen-activated protein kinase pathway leading to cell proliferation. By blocking tumor LA uptake, melatonin effectively blocks the production of 13-HODE and thus, markedly attenuates tumor growth. A similar effect of melatonin is observed in tissue-isolated, ER+ MCF-7 human breast cancer xenografts and nitrosomethylurea (NMU)-induced rat mammary cancers. When male rats bearing tissue-isolated hepatomas are exposed either to constant bright light (300 lux) or dim light (0.25 lux) during the dark phase of a 12L:12D photoperiod, the latency to onset was significantly reduced while the growth of tumors was markedly increased over a 4 wk period as compared with control tumors in 12L:12D-exposed rats. In constant light- and dim light during darkness-exposed rats, melatonin levels were completely suppressed while tumor growth, LA uptake and 13-HODE production were markedly increased. Similar results were obtained in constant bright light-exposed female rats bearing tissue-isolated NMU-induced mammary cancers or MCF-7 human breast cancer xenografts. To date, these studies provide the most definitive experimental evidence that light exposure during darkness increases the risk of cancer progression via elimination of the nocturnal melatonin signal and its suppression of tumor LA uptake and metabolism to 13-HODE.
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PMID:Light during darkness, melatonin suppression and cancer progression. 1216 49

Insulin-like growth factors (IGFs) are potent mitogenic and antiapoptotic factors for many cell types, including some normal and neoplastic lung cells in vitro. However, in this study we show that IGF-I, at concentrations of 10 ng/ml or greater, significantly inhibits DNA synthesis and cell proliferation in a human lung adenocarcinoma cell line, A549. Inhibition of DNA synthesis was completely reversed by an IGF-I receptor-neutralizing antibody, alphaIR-3, indicating that IGF-I receptor activation is involved in its inhibitory effect. Attenuation of the p44/42 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase (PI 3'-kinase) pathways downstream of the IGF-I receptor using the inhibitors PD98059 and LY294002, respectively, partially reversed IGF-I-induced inhibition. Acute (2-60 min) and chronic (24 h) exposure of A549 cells to 100 ng/ml IGF-I resulted in sustained phosphorylation of Akt/protein kinase B downstream of PI 3'-kinase, whereas p44/42 MAPK phosphorylation was decreased in response to chronic exposure to IGF-I. An IGF-I dose-dependent increase in the cyclin-dependent kinase inhibitor p21(Cip1/WAF1) was also observed over 24 h of treatment. Collectively, these data suggest that IGF-I is growth inhibitory to A549 cells, possibly via sustained activation of the PI 3'-kinase signaling pathway, and induction of p21(Cip1/WAF1).
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PMID:Insulin-like growth factor-I inhibits cell growth in the a549 non-small lung cancer cell line. 1220 96

The sphingolipid metabolite, sphingosine-1-phosphate (S1P), formed by phosphorylation of sphingosine, has been implicated in cell growth, suppression of apoptosis, and angiogenesis. In this study, we have examined the contribution of intracellular S1P to tumorigenesis of breast adenocarcinoma MCF-7 cells. Enforced expression of sphingosine kinase type 1 (SPHK1) increased S1P levels and blocked MCF-7 cell death induced by anti-cancer drugs, sphingosine, and TNF-alpha. SPHK1 also conferred a growth advantage, as determined by proliferation and growth in soft agar, which was estrogen dependent. While both ERK and Akt have been implicated in MCF-7 cell growth, SPHK1 stimulated ERK1/2 but had no effect on Akt. Surprisingly, parental growth of MCF-7 cells was only weakly stimulated by S1P or dihydro-S1P, ligands for the S1P receptors which usually mediate growth effects. When injected into mammary fat pads of ovariectomized nude mice implanted with estrogen pellets, MCF-7/SPHK1 cells formed more and larger tumors than vector transfectants with higher microvessel density in their periphery. Collectively, our results suggest that SPHK1 may play an important role in breast cancer progression by regulating tumor cell growth and survival.
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PMID:Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. 1244 Nov 35


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