Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Pancreatic ductal adenocarcinomas (PDACs) overexpress several members of the fibroblast growth factor (FGF) family of ligands and the type I FGF receptor (FGFR-1), and enhanced FGF-2 protein levels correlate with shorter postoperative survival of patients with PDAC. In this study, we investigated the effects of FGF-2 on cell proliferation and mitogen-activated protein kinase (MAPK) activation before and after abrogation of FGFR-1-dependent signaling in 4 pancreatic cancer cell lines (ASPC-1, COLO-357, MIA-PaCa-2, and PANC-1). Signaling was blocked by infecting the cells with an adenoviral vector encoding for a truncated FGFR-1 (AdtrFGFR-1). FGF-2 enhanced the growth of all 4 cell lines and activated MAPK in 3 of these cell lines. Infection with the AdtrFGFR-1 virus resulted in abundant expression of the truncated FGFR-1 at the RNA and protein level, markedly attenuated FGF-2-induced proliferation in all 4 tested cell lines, and decreased FGF-2-dependent MAPK activation in the 3 cell lines in which FGF-2 activated this pathway. These findings suggest that FGFR-1-mediated mitogenesis in multiple pancreatic cancer cells can be efficiently blocked with an adenoviral vector encoding a truncated FGFR-1, raising the possibility that AdtrFGFR-1 may ultimately have a therapeutic role in PDAC.
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PMID:Adenovirus-mediated transfer of a truncated fibroblast growth factor (FGF) type I receptor blocks FGF-2 signaling in multiple pancreatic cancer cell lines. 1470 26

There is a group of cells, called hyalocytes, in the cortical vitreous. Although hyalocytes were discovered more than a hundred years ago, the molecular and cellular biological characteristics of hyalocytes have yet to be elucidated. In this study, we investigated various aspects of hyalocytes and, also performed triamcinolone acetonide (TA)-assisted vitrectomy to remove the hyalocytes for diabetic macular edema. Immunohistochemical analysis of rat eyes showed that 90% of hyalocytes were negative for ED1 but positive for ED2, indicating that hyalocyte is a tissue macrophage. Chimeric mice were created by transplanting bone marrow from green fluorescent protein (GFP)-transgenic mice into irradiated wild-type mice, showing the origin of hyalocyte to be bone marrow cells. Bovine hyalocytes were cultured successfully. The proliferation of hyalocytes was significantly enhanced by hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF-2) and inhibited by transforming growth factor(TGF)-beta. Among these, PDGF-BB stimulated the proliferation most potently through the MEK 1 pathway. Hyalocyte migration assessed by double chamber assay was also stimulated by PDGF-BB and it was mediated by the PI3K and p38 MAPK pathways. Cellular contraction of hyalocyte was significantly enhanced by PDGF-BB and TGF-beta through Rho kinase, p44/42 MAPK, and protein kinase C pathways, as measured by collagen gel contraction assay. Next, the relationship between the vitreous cavity(VC) and the immune system was studied after intravitreous inoculation with ovalbumin (OVA). Injection of OVA into the VC of C 57 BL/6 mice resulted in suppressed systemic cell-mediated immunity to OVA as determined by the ear swelling assay. This aberrant immune responsiveness following VC injection of OVA was termed VC-associated immune deviation or VCAID. The phenomenon of VCAID was mediated by intravitreous antigen-presenting cells. The histological study of chimeric mice showed these cells to be intravitreous residential cells, namely hyalocytes. VCAID was abolished by intravitreous inflammation such as experimental autoimmune uveitis. Finally, TA-assisted vitrectomy for diabetic macular edema was performed to remove cortical vitreous, because it contained many hyalocytes which could secrete inflammatory cytokines including VEGF. Although the number of treated eyes was limited, the surgical results have been favorable so far. The investigation of hyalocytes would open a new avenue for better understanding and development of treatment for various vitreo-retinal diseases.
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PMID:[Cell biology of hyalocytes]. 1473 34

Sphingosine-1-phosphate (S1P) is a lipid mediator that exerts multiple cellular functions through activation of G-protein-coupled receptors. Although the role of S1P on angiogenesis is well established, its role in neurogenesis is unknown. We examined the effects of S1P on G-protein activation in brain sections of rat embryo and on neural progenitor cells in culture. Intense S1P-stimulated [35S]GTPgammaS labeling was observed as early as E15 in the neuroepithelium and differentiating fields throughout the brain, suggesting that functional S1P receptors are expressed in brain areas with active neurogenesis. mRNA transcripts for several S1P receptor subtypes (S1P1, S1P2, S1P3 and S1P5) were expressed in neural progenitor cells prepared from embryonic rat hippocampus. S1P induced phosphorylation of extracellular signal-regulated kinase (ERK) and proliferation of neural progenitor cells as determined by BrdU incorporation in a pertussis toxin-sensitive manner. These effects were prevented by the ERK signaling inhibitor U0126. S1P augmented telomerase activity in neural progenitor cells with similar potency as that of FGF-2. Furthermore, S1P induced cell-cell aggregation. This morphological change was transient and prevented by Y-27632, an inhibitor of Rho-associated kinase. These results suggest that S1P plays a pleiotropic role in neurogenesis via pathways involving S1P receptors, MAP kinases and Rho kinase.
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PMID:Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. 1475 25

Undersulfation of the basement membrane matrix of alveolar type II (AT2) cells compared with that of neighboring type I cells is believed to account for some of the known morphological and functional differences between these pneumocytes. Heparin, a model for sulfated components of basement membrane matrices, is known to inhibit fibroblast growth factor (FGF)-2-stimulated DNA synthesis as well as gene expression of FGF-2 and its receptor in AT2 cells. To determine whether these end points result from specific effects of heparin on FGF-related signaling pathways, isolated rat AT2 cells were treated with 100 ng/ml FGF-1 or FGF-2 in the presence of up to 500 microg/ml heparin. In addition, experiments were done on cells grown in the presence of 20 mM sodium chlorate (sulfation inhibitor). High-dose heparin reduced FGF-1- or FGF-2-stimulated phosphorylation of mitogen-activated protein kinase kinases (MEK1/2), p44/42 mitogen-activated protein kinases (MAPK/ERK1/2), stress-activated protein kinase/c-Jun NH(2)-terminal kinase, Akt/protein kinase B, and p90(RSK). FGF-2-stimulated signaling was more sensitive to heparin's effects than was signaling stimulated by FGF-1. Heparin had an additive effect on the reduced [(3)H]thymidine incorporation in FGF-2-treated AT2 cells caused by inhibition of the MEK/ERK pathway by the MEK inhibitor PD-98059. The data suggest that heparin's known capacity to alter DNA synthesis and, possibly, other biological end points is realized via cross talk between multiple signaling pathways.
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PMID:Heparin affects signaling pathways stimulated by fibroblast growth factor-1 and -2 in type II cells. 1496 81

Recently, we cloned a novel sulfatase domain-containing downregulated gene, HSulf-1, which modulates heparin-binding growth factor signaling in ovarian cancer. Based on the pilot data showing the loss of HSulf-1 in head and neck squamous cell carcinoma cell lines (SCCHN), we sought to employ SCCHN as a model to define the role of HSulf-1 in the molecular regulation of tumorigenicity. Three SCCHN lines (012SCC, WMMSCC, and 015SCC) had no detectable HSulf-1 mRNA. Clonal lines of HSulf-1-expressing 012SCC attenuated the activation of ERK/mitogen-activated protein kinase (MAPK) signaling mediated by fibroblast growth factor (FGF-2) and both ERK/MAPK and Akt signaling mediated by hepatocyte growth factor (HGF). Consistent with this downregulation, phosphorylation of HGF receptor, c-Met, which is frequently overexpressed in SCCHN, was also attenuated in HSulf-1 clonal 012SCC cell lines. HGF markedly enhanced the motility and migration of vector-transfected cells in a transwell invasion chamber. However, HGF-mediated motility and invasion was attenuated in HSulf-1 clonal 012SCC cell lines. In addition, transfected cells displayed significant growth inhibition concomitant with a decrease in mitogenicity, as measured by thymidine incorporation and increased sensitivity to staurosporine- and cisplatin-induced apoptosis. These data suggest that HSulf-1 normally functions as a negative regulator in cell growth and loss of HSulf-1 in SCCHN potentiates growth factor signaling, enhances motility, invasiveness and inhibits stress-induced apoptosis, with a resulting increase in tumorigenicity.
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PMID:HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma. 1497 53

Mitogen-activated protein kinases (MAPKs) are regulated by MAPK kinases (MKKs), which are in turn regulated by MKK kinases (MKKKs). While a single MKKK can regulate several different MAPK family members, and several MKKKs can often activate the same MAPK, emerging evidence indicates a unique role for individual MKKKs in acting as signaling nodes to coordinately activate different subsets of MAPKs in response to specific cellular stimuli. Thus, while there is much apparent overlap in MAPK regulation by different MKKKs, each MKKK serves a specific purpose in regulation of unique cellular functions. The purpose of this study was to define the specific role of MEKK2, an MKKK, in MAPK regulation and cell function. MEKK2 coordinately activates the ERK5 and JNK pathways. Targeted disruption of MEKK2 expression causes loss of ERK5 and JNK activation in response to FGF-2 in mouse embryonic fibroblasts (MEFs). FGF-2 receptor signaling requires MEKK2 for induction of mRNA for c-Jun, Fra-1, and Fra-2, components of the AP-1 transcription complex. In FGF-2-stimulated MEKK2-/- fibroblasts, c-Jun phosphorylation is inhibited, consistent with a loss of JNK activation. Thus, MEKK2 regulates AP-1 activity at two levels, by regulating both expression of AP-1 components and c-Jun N-terminal phosphorylation. One function of the AP-1 transcription complex is to regulate cytokine gene expression. Expression of IL-1alpha, IL-1beta, IL-6, and TNFalpha is inhibited in MEKK2-/- fibroblasts. Bacterial lipopolysaccharide (LPS) and TNFalpha neither activate ERK5 nor require MEKK2 for JNK activation, demonstrating specificity of MEKK2 in FGF-2 receptor signaling and control of cytokine gene expression.
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PMID:MEKK2 regulates the coordinate activation of ERK5 and JNK in response to FGF-2 in fibroblasts. 1497 43

Lens major intrinsic protein (MIP), exclusive to the vertebrate lens, otherwise known as MIP26 and Aquaporin 0, is abundantly expressed as a lens fiber membrane protein. Although relatively less efficient compared with other aquaporins, MIP is suggested to function as a water channel, as an adhesion molecule, and is required for lens transparency. Because MIP is specifically expressed in lens fiber cells, we investigated in this study the activation of Mip expression after triggering differentiation of rat lens epithelia explants by fibroblast growth factor (FGF)-2. Here, we show that Mip expression in the lens cells is regulated by FGF-2. Using Real time PCR we demonstrate that endogenous Mip levels in the explants were up-regulated upon FGF-2 stimulation, in a concentration-dependent manner. Up-regulation of Mip at the transcriptional level was simultaneous with the activation of the FGF down-stream signaling components, ERK1/2 and JNK. Specific inhibitors, UO126 for ERK1/2 and SP600125 for JNK, abrogated Mip expression in response to FGF-2 in the explants. This inhibition pattern was recapitulated in reporter assays for transfection of the rat lens epithelia explants, driven by the Mip promoter (-1648/+44). Our studies show that ERK1/2 and JNK signaling pathways are required for Mip expression in lens epithelia explants induced to differentiate by FGF-2.
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PMID:Lens major intrinsic protein (MIP)/aquaporin 0 expression in rat lens epithelia explants requires fibroblast growth factor-induced ERK and JNK signaling. 1514 28

Amyloid beta peptides (Abeta) form insoluble aggregates in Alzheimer's disease. Accumulation of misfolded amyloid fibrils is generally believed to be a key pathogenic event in several brain disorders. Here we show that small amounts of Abeta peptides activate angiogenesis by promoting endothelial cell proliferation and migration as well as pseudocapillary formation. Abeta peptides functionally synergize with fibroblast growth factor (FGF-2) to promote c-Raf and ERK1/2 activation and angiogenesis in vivo. Thus, Abeta peptides at nanomolar concentrations prime FGF-2 effects on the endothelium, enhancing survival and sustaining angiogenesis. The angiogenesis promoted by Abeta peptides via FGF-2 might have implications for understanding the initial stages of Alzheimer's disease and for the design of therapies targeting beta amyloid.
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PMID:Physiological levels of amyloid peptides stimulate the angiogenic response through FGF-2. 1544 10

Activator protein 1 (AP-1) transcription factor dimers are composed of Jun, Fos, and ATF member proteins, but the mechanisms that determine AP-1 composition are not clearly defined and the function of specific dimers is not well understood. MEKK1 is a mitogen-activated protein kinase (MAPK) kinase kinase and an ubiquitin ligase that regulates both the extracellular signal-regulated kinase 1/2 and the c-Jun amino-terminal kinase. Herein, we demonstrate that MEKK1 regulates the AP-1 protein repertoire. Both FGF-2 and phorbol ester-inducible urokinase-type plasminogen activator (uPA) expression requires AP-1 binding to an enhancer element in the uPA promoter, and we have previously shown that FGF-2 or PMA induction of uPA expression is strongly dependent on MEKK1. JunB mRNA is significantly increased in MEKK1-/- cells, demonstrating that MEKK1 suppresses JunB mRNA expression. Upregulation of JunB expression in MEKK1-/- cells forms an inhibitory AP-1 complex that binds to the uPA promoter and inhibits uPA transcription. MEKK1 also regulates Fra-2 protein stability by inducing Fra-2 ubiquitination and degradation. MEKK1 regulates AP-1-dependent gene expression by regulating the expression, activity and degradation of component members of the AP-1 complex. Controlling the repertoire of a transcription factor complex is a newly defined function for an MAPK kinase kinase.
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PMID:MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability. 1555 21

Tumor cells frequently synthesize an N-terminally extended the FGF-2 isoform of 24 kDa devoid of signal peptide but that contains a functional nuclear localization sequence (NLS). Although the signaling pathways elicited by secreted FGF-2 are well described, the molecular mechanisms involved in the growth promoting action of nuclearized 24 kDa FGF-2 remain unknown. The cancer cell line AR4-2J was engineered to stably express only the 24 kDa FGF-2 isoform and cDNA microarrays were used to identify targets implicated in the intracrine-induced cell proliferation. Levels of 27 transcripts were found either upregulated or downregulated compared to control cells. Among the 18 upregulated genes was c-jun, which is often involved in cell proliferation. Real-time PCR and Western blot analyses confirmed c-jun induction at both mRNA and protein levels. The c-jun antisense oligonucleotide strategy pointed out the involvement of c-Jun in the 24 kDa FGF-2-induced cell proliferation. The mitogenic effect was found to depend on ERK pathway and not on phosphoinositide 3-kinase, p38 MAPK, c-Jun NH2-terminal kinase signal transducers. In addition, the MEK inhibitor PD98059 reduced the 24 kDa FGF-2-dependent c-Jun level. These data show that intracrine FGF-2-mediated regulation of cell growth involves ERK activation and consequent c-Jun expression. Thus, despite its incapacity to be secreted, the intracellular-localized 24 kDa FGF-2 can activate a growth-related signaling pathway normally elicited by cell surface receptors.
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PMID:Identification of c-Jun as a critical mediator for the intracrine 24 kDa FGF-2 isoform-induced cell proliferation. 1560 98


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