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)

Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGFR) have been implicated in the tumorigenesis of a variety of human cancers. Effective tumor inhibition has been achieved both experimentally and clinically with a number of strategies that antagonize either receptor activity. Here we constructed and produced two fully human recombinant bispecific antibodies (BsAb) that target both EGFR and IGFR, using two neutralizing human antibodies originally isolated from a phage display library. The BsAb not only retained the antigen binding capacity of each of the parent antibodies, but also were capable of binding to both targets simultaneously as demonstrated by a cross-linking enzyme-linked immunosorbent assay. Furthermore, the BsAb effectively blocked both ligands, EGF and IGF, from binding to their respective receptors, and inhibited tumor cell proliferation as potently as a combination of both the parent antibodies. More importantly, the BsAb were able to completely block activation of several major signal transduction molecules, including Akt and p44/p42 MAP kinases, by both EGF and IGF, whereas each individual parent antibody was only effective in inhibiting those signal molecules activated by the relevant single growth factor. The BsAb molecules retained good antigen binding activity after incubation with mouse serum at 37 degrees C for up to 6 days. Taken together, our results underscore the benefits of simultaneous targeting multiple growth factor receptor pathways for more efficacious cancer treatment. This report describes the first time use of a recombinant BsAb for targeting two tumor-associated molecules on either a single or adjacent tumor cells for enhanced antitumor activity.
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PMID:Simultaneous blockade of both the epidermal growth factor receptor and the insulin-like growth factor receptor signaling pathways in cancer cells with a fully human recombinant bispecific antibody. 1457 53

Epidemiological data indicate that exposure to metal and metalloid species, including arsenic(III), chromium(VI), and nickel(II), increases the risk of cancer, particularly of the lung and skin. Alterations in normal signal transduction as a result of exposure to carcinogenic metals, and to metal-catalyzed reactive oxygen species (ROS) formation, appear to play an important role in the etiology of metal-induced carcinogenesis. Signaling components affected by metals include growth factor receptors, G-proteins, MAP kinases, and nuclear transcription factors. This article reviews current literature on the effects of carcinogenic metals and metal-induced ROS on cancer-related signaling pathways. In addition, the mechanisms by which those changes occur, and the role of those changes in carcinogenesis are discussed.
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PMID:Signaling by carcinogenic metals and metal-induced reactive oxygen species. 1464 20

Multiple Myeloma (MM) is a progressive malignancy with poor prognosis, commonly treated by the use of the glucocorticoid Dexamethasone. Myeloma cells resist Dexamethasone induced apoptosis when exposed to IL-6 or IGF-1, both of which are known to activate several signaling cascades. For the first time, we show the actual contribution of downstream mediators, i.e., activated STAT factors, independent of the contribution of their upstream signaling pathways, on the proliferation and Dexamethasone rescue effects of IL-6 and IGF-1 in Multiple Myeloma. Retroviral transduction of cytokine dependent myeloma cells with activated STAT transcription factor constructs overcomes the cells dependence on cytokines for growth, allowing proliferation even in very low serum levels. However, the rescue of these previously cytokine dependent cells with activated STATs does not result in an increase in resistance to Dexamethasone induced apoptosis. Despite the presence of activated STAT3 and STAT5a, apoptosis is induced upon exposure to micromolar levels of Dexamethasone, and IL-6 or IGF-1 is still required to rescue the cells. The ability of these factors to block apoptosis is abrogated by the addition of PI-3 Kinase specific inhibitors, but not inhibitors that target the MAP Kinase pathway. However, ectopic expression of activated STAT3 results in partial rescue from apoptosis of cells treated with FAS ligand. Our data suggests that mechanisms of resistance to induced apoptosis and cellular proliferation are separate and distinct in cytokine dependent myeloma cells.
Cancer Biol Ther 2004 Feb
PMID:Activating mutations in STAT3 and STAT5 differentially affect cellular proliferation and apoptotic resistance in multiple myeloma cells. 1497 30

Ras proteins regulate cell growth and differentiation, and their mutation plays a major, direct role in causing human cancer. For years, their precise function has been a mystery. One of the pathways Ras controls has recently been identified. It consists of a cascade of kinases (Raf, MEK and MAP kinases) that transmits signals from the plasma membrane to the nucleus. The role of Ras is remarkably simple: it recruits Raf from the cytoplasm to the plasma membrane. Once in the membrane, Raf is activated and the kinase cascade is initiated. Is this the whole story?
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PMID:Raf: the holy grail of Ras biology? 1473 20

Aromatase (estrogen synthetase) inhibitors are superior to tamoxifen in terms of both efficacy and toxicity in the treatment of advanced breast cancer and also in the neoadjuvant setting. Recent results from the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial showed a marked reduction in contralateral primary breast cancer with anastrozole, an apparent prevention effect. A similar effect was seen in the MA.17 adjuvant trial comparing letrozole with placebo after 5 years of adjuvant tamoxifen. This has accelerated interest in aromatase inhibitors as primary preventive therapy. Two studies being conducted by the National Cancer Institute of Canada's Clinical Trials Group select women by virtue of mammographic breast density. The International Breast Cancer Intervention Study 2 trial randomizes women at elevated risk to anastrozole or placebo. Because of its steroidal structure, exemestane may be more effective than the nonsteroidal aromatase inhibitors and may protect bone and lipid metabolism from the effects of estrogen ablation. Elevated prostaglandin E2 levels from cyclooxygenase-2 induction by preinvasive and invasive breast lesions increase a number of tumor-promoting pathways, including aromatase, as well as angiogenetic, antiapoptotic, and others. Additive or synergistic effects between celecoxib, a cyclooxygenase-2 inhibitor, and exemestane have been demonstrated and have led to the National Cancer Institute of Canada's Clinical Trials Group MAP.3 trial, which will randomize women at elevated risk to placebo or to exemestane with or without celecoxib. The efficacy and long-term toxicity data from the aromatase inhibitor prevention trials, and the identification of risk profiles from trial results, are awaited with interest.
Clin Cancer Res 2004 Jan 01
PMID:Prevention strategies with aromatase inhibitors. 1473 94

Several studies reported linkage between bacterial infections and carcinogenesis. Streptococcus bovis was traditionally considered as a lower grade pathogen frequently involved in bacteremia and endocarditis. This bacterium became important in human health as it was shown that 25-80% of patients who presented a S.bovis bacteremia had also a colorectal tumor. Moreover, in previous experiments, we demonstrated that S.bovis or S.bovis wall extracted antigens (WEA) were able to promote carcinogenesis in rats. The aim of the present study was: (i) to identify the S.bovis proteins responsible for in vitro pro-inflammatory properties; (ii) to purify them; (iii) to examine their ability to stimulate in vitro IL-8 and COX-2 expression by human colon cancer cells; and (iv) to assess in vivo their pro-carcinogenic potential in a rat model of colon carcinogenesis. The purified S300 fraction, as determined by proteomic analysis, contained 72 protein spots in two-dimensional gel electrophoresis representing 12 different proteins able to trigger human epithelial colonic Caco-2 cells and rat colonic mucosa to release CXC chemokines (human IL-8 or rat CINC/GRO) and prostaglandins E2, correlated with an in vitro over-expression of COX-2. Moreover, these proteins were highly effective in the promotion of pre-neoplastic lesions in azoxymethane-treated rats. In the presence of these proteins, Caco-2 cells exhibited enhanced phosphorylation of the three classes of MAP kinases. Our results show a relationship between the pro-inflammatory potential of S.bovis proteins and their pro-carcinogenic properties, confirming the linkage between inflammation and colon carcinogenesis. These data support the hypothesis that colonic bacteria can contribute to cancer development particularly in chronic infection/inflammation diseases where bacterial components may interfere with cell function.
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PMID:Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). 1474 16

Activation of MAP kinases is involved in various cellular processes, including immunoregulation, inflammation, cell growth, cell differentiation, and cell death. To investigate the role of p38 MAP kinase activation in the signaling pathway of TRAIL-mediated apoptosis, we compared TRAIL-mediated MAP kinase activation in TRAIL-susceptible human colon cancer cell line DLD1 and TRAIL-resistant DLD1/TRAIL-R cells. TRAIL-mediated activation of ERK occurred in both cell lines. In contrast, both DLD1 and DLD1/TRAIL-R cells showed no obvious JNK activation after treatment with TRAIL. Interestingly, TRAIL-mediated activation of p38 MAP kinases was observed in DLD1 cells but not in DLD1/TRAIL-R cells. However, activation of p38 MAP kinases was observed in both DLD1 and DLD1/TRAIL-R cells after treatment with anisomycin. Furthermore, inhibiting activated p38 MAP kinases with known inhibitors or with an adenovector expressing dominant negative p38alpha did not block TRAIL-mediated cell death in DLD1 cells. Moreover, activation of p38 MAP kinases by adenovectors expressing constitutive MKK3 or MKK6 (Ad/MKK3bE or Ad/MKK6bE) did not induce cell death in either DLD1 or DLD1/TRAIL-R cell lines. Our results suggest that activation of p38 MAP kinases does not play a major role in TRAIL-mediated apoptosis in DLD1 cells and that lack of TRAIL-mediated p38 MAP kinase activation may not be the mechanism of TRAIL-resistance in DLD1/TRAIL-R cells.
Cancer Biol Ther 2004 Mar
PMID:Lack of p38 MAP kinase activation in TRAIL-resistant cells is not related to the resistance to TRAIL-mediated cell death. 1510 6

The p53 tumor suppressor protein exerts its growth inhibitory activity by activating and interacting with diverse signaling pathways. As a downstream target, p53 protein is phosphorylated and activated by a number of protein kinases in response to stressful stimuli. As an upstream activator, activated p53 acts as a transcription factor to induce and/or suppress a number of genes whose expression leads to the activation of diverse signaling pathways. p53 protein can also interact with a number of proteins, resulting in an increase or decrease in p53 activity itself. The activation of p53 leads to many outcomes in cells, including cell cycle arrest and apoptosis. It has become clear that the p53 protein can functionally interact with the mitogen-activated protein kinase (MAPK) pathways, including the stress-activated protein kinase [SAPK/c-Jun N-terminal protein kinase (JNK)], the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal related kinase (ERK). Upon exposure to stressful stimuli, MAP kinases phosphorylate and activate p53, leading to p53-mediated cellular responses. Recent studies have suggested a role of p53 as an upstream activator to regulate MAPK signaling via the transcriptional activation of members of the dual specificity phosphatase family. Because both the p53 and MAPK signaling pathways are altered in the majority of human tumors, understanding their functional interaction may provide new insights into the deregulated cell proliferation and survival that is characteristic of cancer.
Cancer Biol Ther 2004 Feb
PMID:The functional interactions between the p53 and MAPK signaling pathways. 1476 89

We previously identified an H-2L(d)-binding peptide pRL1a (IPGLPLSL) on RL male 1 that is predominantly recognized by cytotoxic T-lymphocytes (CTLs). MAP is a multibranched lysine core with antigenic peptides. Immunization of BALB/c mice with pRL1a MAP effectively induced pRL1a CTLs. Here, we demonstrate the presence of pRL1a-recognizing CD8(+) T-cells in pRL1a MAP-immunized and RL male 1-bearing BALB/c and (BALB/c x C57BL/6)F(1) mice by using IFNgamma ELISPOT and H-2L(d)/pRL1a tetramer assays. A few IFNgamma ELISPOTs and no tetramer-positive cells were detected ex vivo in spleen cells from BALB/c mice immunized with pRL1a MAP. After a single in vitro stimulation with RL male 1, 432 and 741 IFNgamma ELISPOTs/10(5) cells were detected and tetramer-positive CD8(+) T-cells occurred at relative frequencies of 5.7% and 30.8% in splenic CD8(+) T-cells from mice that had been doubly and triply immunized, respectively, against pRL1a MAP. Tetramer-positive cells displayed two distinct cell populations, CD62L(low) and CD62L(high). Secondary in vitro stimulation expanded CD62L(high) cells more efficiently than CD62L(low) cells. Furthermore, a higher frequency of IFNgamma-producing and tetramer-positive CD8(+) T-cells was detected ex vivo in RL male 1-bearing semi-allogeneic (BALB/c x C57BL/6)F(1) than in BALB/c mice on day 14 after tumor inoculation.
Cancer Sci 2004 Mar
PMID:Analysis of CD8 T-cell response by IFNgamma ELISPOT and H-2L(d)/pRL1a tetramer assays in pRL1a multiple antigen peptide-immunized and RL male 1-bearing BALB/c and (BALB/c x C57BL/6) F(1) mice. 1501 26

To look for new candidates for agents to use in maintenance therapy for myeloma patients, the growth inhibitory effects of a 3-hydroxy-3-mehtylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin), simvastatin, was analyzed using human myeloma cell lines. Several investigations have indicated growth reduction in certain lineages of cancer cells including one report on myeloma, and inhibitory effects of statins on GTPases and involving MAP-kinases. Most (12 out of 13) myeloma lines examined showed growth inhibition when cultured with various concentrations (1-30 microM) of simvastatin in a dose-dependent manner. Simvastatin in combination with other biological response modifiers such as ATRA or DEX had additional effects on growth. In addition, anti-oxides prevented the simvastatin-induced growth inhibition and apoptosis. Furthermore, myeloma cells treated with simvastatin clearly showed inactivation of various MAP-kinase pathways such as ERK1/2, MEK1/2, JNK, and p38. Based on these findings, statins may be suitable for clinical usage in maintenance therapy for myeloma patients.
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PMID:Effects of an HMG-CoA reductase inhibitor, simvastatin, on human myeloma cells. 1506 46


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