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)

The Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1), an oncogenic protein, plays an important role in the carcinogenesis of nasopharyngeal carcinoma (NPC). Phosphorylation of p53 protein is likely to play the key role in regulating its activity. p53 protein accumulates but mutation of p53 gene is not common in NPC. The molecular mechanisms of p53 augmentation have not been completely elucidated. Here, the role of MAP kinases in the phosphorylation of p53 modulated by LMP1 was determined. p53 could be activated and phosphorylated clearly at Ser15, Ser20, Ser392, and Thr81 modulated by LMP1. Furthermore, LMP1-induced phosphorylation of p53 at Ser15 was directly by ERKs; at Ser20 and Thr81 by JNK, at Ser 15 and Ser392 by p38 kinase. The phosphorylation of p53 was associated with its transcriptional activity and stability modulated by LMP1. These results strongly suggest that MAP kinases have a direct role in LMP1-induced phosphorylation of p53 at multiple sites, which provide a novel view for us to understand the mechanism of the activation of p53 in the carcinogenesis of nasopharyngeal carcinoma.
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PMID:Latent membrane protein 1 of Epstein-Barr virus regulates p53 phosphorylation through MAP kinases. 1758 79

Regulation of the synthesis, function and degradation of HDM2 (Mdm2 in mouse) plays a key role in controlling the abundance and activity of the transcription factor p53, with consequent implications for the proliferation and survival of normal and cancer cells. We have previously identified the regulation of export of HDM2 mRNA from the nucleus as a novel point of control of HDM2 synthesis. This process is dependent on the activity of the growth factor-regulated MAP-kinase kinases (MEKs). Here, we provide evidence that the eIF4E kinase MNK1 is a key downstream effector of MEKs in this regulatory pathway. We show that HDM2 mRNA export in breast cancer cells is promoted by overexpressed eIF4E in a MEK- and MNK1-dependent manner, and inhibition of MNK1 suppresses endogenous HDM2 mRNA export pathways. This MNK1- and eIF4E-dependent HDM2 regulation occurs through sequences in the 3' untranslated region of HDM2 mRNA, and consequently HDM2 mRNA transcripts from both the constitutive P1 and inducible P2 promoters are regulated by this pathway. eIF4E is a known oncogene that is overexpressed in human tumours, including the majority of breast cancers. This pathway, therefore, may play an important role in the dysregulation of HDM2 oncoprotein expression that occurs in many human tumours.
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PMID:MNK1 and EIF4E are downstream effectors of MEKs in the regulation of the nuclear export of HDM2 mRNA. 1782 1

In the intestinal mucosa of pig, calf and rat neonates, we observed the cells die in the packets which suggests involvement of some paracrine factors. The death signal was transferred via tissue continuum as well as across the gut lumen, and the involvement of TGF-beta1 and TNFalpha was demonstrated. Present study aimed to clarify the molecular mechanisms of programmed cell death in the mucosa of the small intestine of pig neonates. Groups (packets) of cells and the neighboring cells underwent apoptosis, and expressed an enhanced TGF-RII. In the dying cells the death signal promoted via TGF-RII was associated with enhanced expression of active caspase 8, TGF-beta1, TNFalpha and Bid. Quantitative study showed that high expression of TGF-beta1 was positively correlated with expression of BID and negatively with BCL-2, illustrating the transmission of signal from TGF-RII through SMAD cascade and RunX protein. We hypothesize that TGF-beta1 sensitizes the enterocytes for TNFalpha signaling and both cytokines control the apoptosis process in the gut epithelium. Intensive mitosis triggers many errors in DNA replication, and the role of p53 is to detect them and promote either repair or apoptosis. During first days of live all damaged cells were directed towards apoptosis while at day 7 at least some of them were repaired. Autophagy, the second form of programmed cell death, was recognized by its key marker MAP I LC3. Our data showed the colocalization of MAP I LC3 with active caspase 3 thus suggesting a coexistence between these two forms of cell death, at least in the early postnatal life.
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PMID:Molecular mechanism of programmed cell death in the gut epithelium of neonatal piglets. 1790 86

Development of the small intestinal epithelium in early postnatal period has a significant influence on pig's survival rate and further productivity. The aim of this research was to verify whether the diet supplementation of pregnant and lactating sow with a blend of bioactive substances (flax seed, rapeseed, linden inflorescence, taurine, L-carnitine and tocopherol acetate) had an effect on the development of intestinal epithelium in their offspring. The doses of bioactive substances were calculated to meet the demands for optimal supply of the pig fetuses and newborns. Pig neonates from two groups of sows, control and supplemented, were sacrificed at the day 1, 2, 4, 7 and 14 of life. The samples taken from mid-jejunum were evaluated for mitosis (Ki67), apoptosis (active caspase 3), autophagy (MAP I LC3), and DNA damage (p53). Increase of mitotic index was noticed at day 1, 4 and 7 for supplemented group when compared to the control. Reduction of apoptotic index was observed at day 2 as compared to control. A tendency toward elevated autophagy was observed during the first 2-4 postnatal days in both groups. p53 expression was significantly lower in supplemented group as compared to control. Overall, the mitosis to programmed cell death ratio was increased and the maturation of epithelial cells quickened. We suppose that the supplementation of pregnant and lactating sow diet with bioactive substances enhanced maturation of the small intestinal epithelium in their offspring during the early postnatal period.
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PMID:The effect of supplementing sow with bioactive substances on neonatal small intestinal epithelium. 1790 87

The oncogene HDM2 has been implicated in the regulation of the transcription factor, hypoxia inducible factor (HIF). We show in von Hippel-Lindau (VHL)-defective renal carcinoma cells that express constitutively high levels of HIF-1 alpha and HIF-2 alpha that down-regulation of HDM2 by siRNA leads to decreased levels of both HIF-1 alpha and HIF-2 alpha protein levels. However, we show a differential regulation of HDM2 on the HIF angiogenic targets, vascular endothelial growth factor (VEGF), plasminogen activator inhibitor-1 (PAI-1), and endothelin-1 (ET-1): siRNA to HDM2 leads to increased expression of VEGF and PAI-1 proteins but decreased levels of ET-1. We show that HDM2-mediated regulation of these proteins is independent of VHL and p53 but dependent on a novel action of HDM2. Ablation of HDM2 leads to phosphorylation of extracellular-regulated kinase (ERK)1/2 in renal carcinoma cells. We show that regulation of these angiogenic factors is dependent on ERK1/2 phosphorylation, which can be reversed by addition of the MAP/ERK1/2 kinase inhibitors PD98059 and PD184352. This study identifies a novel role for the HDM2 oncoprotein in the regulation of angiogenic factors in renal cell carcinoma.
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PMID:Regulation of angiogenic factors by HDM2 in renal cell carcinoma. 1819 51

JNK and ERK MAP kinases regulate cellular responses to genotoxic stress in a cell type and cell context-dependent manner. However, the factors that determine and execute JNK- and ERK-controlled stress responses are only partly known. In this study, we investigate the roles of the AP-1 components ATF3 and Fra1 in JNK- and ERK-dependent cell cycle arrest and apoptosis. We show that the anti-cancer drug cisplatin or UV light activates both JNK and ERK in human glioblastoma cells lacking functional p53. Inhibition experiments of JNK or ERK activities revealed that the ERK pathway strongly promotes cisplatin- and UV-induced apoptosis in these glioblastoma cells. Furthermore, JNK but not ERK is required for ATF3 induction, and both ERK and JNK are necessary for post-transcriptional induction of Fra1 in response to cisplatin or UV. Knock-down of ATF3 and Fra1 results in increased and decreased cisplatin-induced apoptosis, respectively, indicating that ATF3 is an anti-apoptotic JNK effector and Fra1 is a pro-apoptotic ERK/JNK effector. Knock-down experiments also revealed that ATF3 and Fra1, respectively, enhance and reduce S-phase arrest through differential modulation of the Chk1-Cdk2 pathway. Thus, we identify novel reciprocal functions of ATF3 and Fra1 in JNK- and ERK-dependent DNA damage responses.
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PMID:ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses. 1824 59

We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.
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PMID:Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas. 1832 52

With only few exceptions that include Hes-1 p53, and IkappaB, the expression of genes has never been shown to be oscillatory. Here, we show that the inflammatory cytokine TNF triggers oscillations in >5000 genes. We utilize microarrays at 30-min intervals to analyze the pattern of global gene expression in murine macrophages. We find that 15% of genes in the genome underwent a significant >3-fold increase in expression, with 89% of these displaying oscillations at frequencies as low as every 50min. We analyze further two sub-clusters of genes that either began oscillating early or after a lag phase. Through the use of quantitative PCR, we confirm the oscillations and show that the oscillations are continuous. Moreover, we show that these continuous oscillations are not unique to TNF, but that related cytokines such as RANK-L produces oscillations with a unique induction profile. In the two papers accompanying this one, we analyze the mechanism of these oscillations and find that TNF also triggers oscillations in the phosphorylation of MAP kinases, and that these oscillations combine to recruit transcription factors to promoters in a cyclical fashion. The results presented here suggest that gene transcription is a highly dynamic processes, with thousands of genes displaying rapid (<60min) oscillations over time. Considering this dynamism, time-resolved measurements of gene transcription should become the experimental norm.
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PMID:TNF-induced gene expression oscillates in time. 1838 46

The metastasis-promoting protein S100A4 stimulates metastatic progression through both intracellular and extracellular functions. Extracellular activities of S100A4 include stimulation of angiogenesis, regulation of cell death and increased cell motility and invasion, but the exact molecular mechanisms by which extracellular S100A4 exerts these effects are incompletely elucidated. The aim of the present study was to characterize S100A4-induced signal transduction mechanisms and to identify S100A4 target genes. We demonstrate that extracellular S100A4 activates the transcription factor NF-kappaB in a subset of human cancer cell lines through induction of phosphorylation and subsequent degradation of the NF-kappaB inhibitor IkappaBalpha. Concomitantly, S100A4 induced a sustained activation of the MAP kinase JNK, whereas no increased activity of the MAP kinases p38 or ERK was observed. Microarray analyses identified 136 genes as being significantly regulated by S100A4 treatment, and potentially interesting S100A4-induced gene products include IkappaBalpha, p53, ephrin-A1 and optineurin. Increased expression of ephrin-A1 and optineurin was validated using RT-PCR, Western blotting and functional assays. Furthermore, S100A4-stimulated transcription of these target genes was dependent on activation of the NF-kappaB pathway. In conclusion, these findings contribute to the understanding of the complex molecular mechanisms responsible for the diverse biological functions of extracellular S100A4, and provide further evidence of how S100A4 may stimulate metastatic progression.
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PMID:Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes. 1854 84

The effect of external zinc supplementation (10 and 35 micromol) on cell proliferation and mitogenic signaling of Hep-2 tumor cells was examined during 72 h of treatment. Zinc levels were manipulated by using zinc-free cultivation medium with or without addition of zinc ions. Proliferation of Hep-2 cells exposed to zinc-free medium decreased in a time-dependent manner and corresponded to decreasing intracellular zinc content. Hep-2 cells accumulated in G(0)/G(1) phase, showed reduced abundance of AKT and NF-kappaB as well as of anti-apoptotic Bcl-2 and Bcl-XL proteins. Zinc supplied to Hep-2 cells maintained in the presence of zinc-free medium stimulated their proliferation as well as mitogenic signaling which paralleled increasing intracellular zinc content. In zinc-exposed Hep-2 cells, several changes in various mitogenic signaling pathways were noted such as enhanced expression of p53, AKT and MAP kinases, NF-kappaB and increased DNA binding of AP-1 family. Also, supplementation with zinc of Hep-2 cells resulted in the suppression of key apoptotic molecules such as Bax protein and increased expression of anti-apoptotic Bcl-2 and Bcl-XL proteins. Since only the highest supplied zinc concentration (35 micromol) induced oxidative stress, it is reasoned that the observed activation of pro-survival signaling occurs both directly and indirectly. These data show that zinc may stimulate growth and proliferation of some tumor cells by a combination of internal mechanisms with a varying contribution of external signaling pathways too.
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PMID:External zinc stimulates proliferation of tumor Hep-2 cells by active modulation of key signaling pathways. 1856 27


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