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

The expression of the angiogenic growth factors, vascular endothelial cell growth factor (VEGF) and placenta growth factor (PIGF) was demonstrated in isolated human term cytotrophoblast and in vitro differentiated syncytiotrophoblast. RNase protection assays demonstrated VEGF expression in both cytotrophoblast and syncytiotrophoblast while prominent PIGF expression was detected in both types of trophoblast by Northern blot analyses. VEGF expression increased approximately eightfold in trophoblast cultured under hypoxic conditions (1 per cent O2) yet PIGF expression decreased 73 +/- 5.5 per cent in the same trophoblast. These results suggest distinct regulatory mechanisms govern expression of VEGF and PIGF in trophoblast. Characterization of the VEGF/PIGF receptors, KDR and flt-1, revealed the presence of flt-1 mRNA in isolated cytotrophoblast and in vitro differentiated syncytiotrophoblast. KDR was not detected in the isolated trophoblast. Exogenous rhVEGF induced c-Jun N-terminal kinase (JNK) activity in the normal trophoblast indicating that the flt-1 receptors on trophoblast are functional. Trophoblast-derived VEGF/PIGF could act in a paracrine fashion to promote uterine angiogenesis and vascular permeability within the placental bed. In addition, presence of function flt-1 on normal trophoblast suggests that VEGF/PIGF functions in an autocrine manner to perform an as yet undefined role in trophoblast invasion, differentiation, and/or metabolic activity during placentation.
Placenta 1997 Nov
PMID:Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast. 936 1

The regulation of cytokine secretion has not been extensively investigated in placental tissue. Fragments of term human placenta were incubated in Tyrode's medium for 3h and cytokine concentrations were measured in the supernatant. IL-1beta secretion after vaginal delivery (VD) was (mean +/- SEM fmol/mg wet weight/3h) 0.193 +/- 0.005 (basal) and 0.549 +/- 0.18 (+1n M TNFalpha) and was more sensitive to TNFalpha dose after elective Caesarean section in the absence of clinical labour (CS) than VD. Secretion of IL-6 after VD was 2.3 +/- 0.47 (basal) and 3.01 +/- 0.34 (+1n M TNFalpha), was correlated with the secretion of IL-1beta and was more sensitive to TNFalpha dose after VD than CS. The inhibitors SB203580, PD98059, SN50, cycloheximide and D-ribofuranosylbenzimidazole each reduced the basal and TNFalpha-stimulated secretion of IL-1beta and also reduced IL-6 secretion with the exception of SN50. There were no interactions between effects of inhibitors and mode of delivery or TNFalpha. In summary we found that term placenta spontaneously secretes IL-1beta and IL-6 in vitro. Delivery after labour alters placental sensitivity to TNFalpha. Exposure to agents known to inhibit MAPK pathways, NF-kappaB, or synthesis of protein and mRNA reduces placental cytokine secretion.
Placenta 2002 Jul
PMID:Secretion of interleukin-1beta and interleukin-6 by fragments of term human placental villi: signalling pathways and effects of tumour necrosis factor alpha and mode of delivery. 1213 44

Neutral endopeptidase 24.11 (NEP) is identical to CD10, which is a differentiation antigen for early B-lymphoid progenitors in the B-cell differentiation pathway. This ectoenzyme is known to have a key role in the control of growth, differentiation, and signal transduction of many cellular systems by regulating bioactive peptides and cytokines. Recently, we demonstrated that NEP/CD10 is upregulated during forskolin-induced choriocarcinoma cell differentiation, suggesting that NEP/CD10 is a trophoblast differentiation marker. The purpose of this study was to clarify the enhancement of NEP/CD10 expression and its signal transduction pathway during phorbol ester (PMA)-induced differentiation of BeWo choriocarcinoma cells. PMA-induced differentiation of BeWo cells was confirmed by morphological change and human chorionic gonadotropin (hCG) secretion, which was completely blocked by a protein kinase C (PKC) inhibitor, Bisindolylmaleimide I (Bis I). On immunoblot analysis, PMA enhanced NEP/CD10 expression in a dose- and time-dependent manner, which was completely abolished by Bis I and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor, PD98059. PMA also induced phosphorylation of p44/p42 extracellular signal-regulated kinases (ERK) 1 and 2. These observations indicated that activation of PKC by PMA induced differentiation of BeWo cells, and that PMA activated MAPK/ERK, which resulted in the enhancement of NEP/CD10 expression. Furthermore, immunocytochemical analysis showed that NEP/CD10 expression was detected on the membranes of PMA-treated differentiated BeWo cells. In summary, we demonstrated that NEP/CD10 was enhanced during PMA-induced differentiation of BeWo choriocarcinoma cells through a PKC-dependent MEK/ERK signalling pathway. Our findings also suggest that NEP/CD10 may play a functional role in the process of trophoblast differentiation.
Placenta 2002 Jul
PMID:Neutral endopeptidase/CD10 expression during phorbol ester-induced differentiation of choriocarcinoma cells through the protein kinase C- and extracellular signal-regulated kinase-dependent signalling pathway. 1213 45

Mitogen-activated protein kinase (MAP kinase) plays a central role in the signal transduction for diverse cellular responses, such as proliferation, differentiation, stress response and cell death, via activation after binding of growth factors to the respective receptors on the cell membrane. In the human placental tissues, however, little is known about the expression and activation of the classical MAP kinases, extracellular signal-regulated kinase1/2 (ERK1/2). We therefore examined the expression of ERK1/2 in the human chorionic and placental tissues between 5 and 41 weeks of gestation, using Western blotting, immunohistochemistry and in situ hybridization. To explore the activation of ERK1/2 protein, we used an antibody that reacts with both phosphorylated and non-phosphorylated ERK1/2 (total ERK1/2), as well as antibodies that react only with phosphorylated ERK1/2. The expression pattern of phosphorylated ERK1/2 in the trophoblasts was compared with that of various growth factor receptors, such as c-met, IGF-1R, flt-1, EGFR, PDGFR, Bek, and flg. Total ERK1/2 was immunolocalized in the villous cytotrophoblasts (CTs), but not in the syncytiotrophoblasts (STs), throughout pregnancy. In situ hybridization also showed the localization of ERK1 mRNA in the villous CTs. Interestingly, however, phosphorylated ERK1/2 was immunolocalized in the villous CTs only up to 12 weeks of gestation. Western blot also showed the stronger bands of phosphorylated ERK1/2 in the tissues of the first trimester. Among the growth factor receptors, c-met was strongly expressed in the villous CTs during the first trimester, and resembled the expression pattern of phosphorylated ERK1/2. These findings suggest that the MAP kinase pathway is activated in the villous CTs during the first trimester in the human placenta.
Placenta
PMID:Expression and activation of MAP kinases, ERK1/2, in the human villous trophoblasts. 1256 43

We have characterized the transduction pathways induced by leptin in the placenta, using human BeWo cells that express endogenous leptin receptors and synthesize leptin in a regulated manner. We first examined if the JAK-STAT phosphorylation cascade was functional in these cells. Phosphorylated JAK2 was primarily bound to a short 106kDa leptin receptor isoform and to a lesser extent to a 210kDa molecule. Leptin neither enhanced JAK2 phosphorylation nor activated STAT3 and STAT1 proteins indicating that JAK2 is constitutively activated and that the JAK-STAT transduction pathway is not recruited by leptin in BeWo cells. By contrast, leptin stimulated the transcription of the c-fos gene (3-fold) and cell proliferation (2-fold) as measured by DNA synthesis. Both effects were dependent on the rapid phosphorylation of p42-44 MAPK but not p38 MAPK. We conclude that a functional JAK-STAT pathway is not required for leptin to transduce proliferative signals in human placental cells. These findings extend the physiological action of leptin beyond its central effects, to the control of placental gene transcription and cell proliferation.
Placenta 2003 Apr
PMID:Transduction of leptin growth signals in placental cells is independent of JAK-STAT activation. 1265 12

Leptin and glucose effect on cell growth has been investigated in the JAr human choriocarcinoma cells. When JAr cells were cultured in the presence of 6m M glucose (LG), proliferation and thymidine incorporation were induced by serum but not by leptin. At variance, at 25m M glucose (HG), proliferation and thymidine incorporation were stimulated by leptin and serum to a comparable extent. HG culturing also enhanced leptin-stimulated insulin receptor substrate 1 (IRS1) and MAPK phosphorylation. Blockage of MAPK activity with PD98059 caused an inhibition of glucose- and leptin-dependent thymidine incorporation. At variance with HG conditions no effects were observed in cells cultured in 6m M glucose upon treatment with PD98059. Neither glucose nor leptin determined a modification in leptin receptors total content. In this study, we provide evidence that in placental cells, leptin, similarly to that observed with insulin, stimulates cell proliferation by inducing the IRS1/MAPK pathway in a glucose-dependent fashion.
Placenta 2003 Apr
PMID:Leptin induces mitogenic effect on human choriocarcinoma cell line (JAr) via MAP kinase activation in a glucose-dependent fashion. 1265 13

Neutral endopeptidase 24.11 (NEP) is known to regulate cellular functions by degrading several bioactive peptides, such as gonadotropin-releasing hormone (GnRH). The present study was performed to clarify the mechanisms of NEP expression by GnRH in human choriocarcinoma (BeWo) cells. GnRH increased NEP expression and enzyme activity in a dose- and time-dependent manner in BeWo cells. The phosphorylation levels of protein kinase C (PKC) delta, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1 and 2) were enhanced after 10 min exposure of 10(-6)m GnRH. The effect of GnRH on both NEP expression and enzyme activity was completely inhibited by inhibitors of PKC, PKC delta, and p38MAPK. Cell number was reduced by 54.4 per cent of the control by culture with 10(-6)m GnRH for 24 h. However, phosphoramidon, a NEP specific inhibitor, inhibited antiproliferative effect of GnRH and reverted to the control level. In conclusion, GnRH induces NEP expression by PKC delta and p38MAPK, and increased NEP expression may be involved in antiproliferative effect in BeWo cells.
Placenta
PMID:Signal pathway involved in increased expression of neutral endopeptidase 24.11 by gonadotropin releasing hormone in choriocarcinoma cells. 1497 50

Increasing evidence supports that many common obstetrical complications may involve the disruption of normal placental and/or uterine vascular function. Placenta growth factor (PlGF) is an angiogenic factor that is abundantly expressed in the placenta, with primary site of synthesis being trophoblast. Receptors for PlGF include products of the fms-like tyrosine kinase (flt-1) gene which is expressed in several cell types including endothelial cells and trophoblast. PlGF activation of flt-1 in trophoblast induces the stress activated protein kinase (SAPK) signal transduction pathways, JNK (c-Jun-N-Terminal Kinase) and p38, with little induction of the extracellular signal-regulated protein kinase (ERK)-1/2 pathways. In contrast, PlGF induces strong ERK-1/2 activation, but little JNK or p38 responses in human umbilical vein endothelial cells (HUVEC). To better understand the biochemical functions of PlGF in trophoblast, we studied upstream signal regulatory molecules to determine those that are responsible for directing the divergent PlGF signal transduction responses in these cell types. PlGF induced similar activation of Nck and PLC-gamma in trophoblast and HUVEC. In marked contrast, SHP-2 and Gab2 were strongly activated by PlGF in endothelial cells but not trophoblast. These results suggest a general role for Nck and PLC-gamma in mediating PlGF signal transduction responses independent of the different downstream MAPK pathways activated. However, SHP-2 and Gab2 are regulatory molecules involved in the PlGF induction of different terminal pathways in HUVEC and trophoblast.
Placenta 2004 May
PMID:Deferential regulation of placenta growth factor (PlGF)-mediated signal transduction in human primary term trophoblast and endothelial cells. 1508 32

The invasive differentiation pathway of trophoblasts is an indispensable physiological process of early human placental development. Formation of anchoring villi, proliferation of cell columns and invasion of extravillous cytotrophoblasts into maternal decidual stroma and vessels induce vascular changes ensuring an adequate blood supply to the growing fetus. Extravillous trophoblast differentiation is regulated by numerous growth factors as well as by extracellular matrix proteins and adhesion molecules expressed at the fetal-maternal interface. These regulatory molecules control cell invasion by modulating activities of matrix-degrading protease systems and ECM adhesion. The differentiation process involves numerous signalling cascades/proteins such as the GTPases RhoA, the protein kinases ROCK, ERK1, ERK2, FAK, PI3K, Akt/protein kinase B and mTOR as well as TGF-beta-dependent SMAD factors. While an increasing number of signalling pathways regulating trophoblast differentiation are being unravelled, downstream effectors such as executing transcription factors remain largely elusive. Here, we summarise our current knowledge on signal transduction cascades regulating invasive trophoblast differentiation. We will focus on cell model systems which are used to study the particular differentiation process and discuss signalling pathways which regulate trophoblast proliferation and motility.
Placenta 2005 Apr
PMID:Signalling pathways regulating the invasive differentiation of human trophoblasts: a review. 1583 62

Epidermal growth factor (EGF) reduces apoptosis in primary cytotrophoblast (CT) in culture through two separate pathways: the extracellular signal related kinase (ERK) 1/2 and phosphatidyl inositol 3-kinase (PI-3 kinase) paths. Whether other pathways are involved in survival signalling is unknown. We here show that the c-Jun NH2 terminal kinase (JNK) and the mitogen activated kinase (MAPK) p38 are also activated by EGF as seen by increases in JNK and p38 phosphorylation. However, inhibition of JNK phosphorylation with the specific inhibitor SP600125 increases apoptosis in a manner refractory to the addition of EGF but inhibition of p38 phosphorylation with its specific inhibitor SB 203580 does not increase apoptosis. EGF also activates sphingosine kinase-1 (SPHK-1), which converts sphingosine to sphingosine-1-phosphate, and its inhibition with dimethyl sphingosine (DMS) increased trophoblast death. Inhibition of SPHK-1 also did not affect EGF stimulated phosphorylation of PI-3 kinase, Akt, ERK1/2 or p38 but inhibition of PI-3 kinase with a specific inhibitor LY294002 partly (40%) inhibited the EGF-stimulated increase in SPHK-1 activity. We conclude that, in addition to the PI-3 kinase and ERK1/2 pathways, EGF acts through its receptor to stimulate JNK, p38 and SPHK-1 pathways, but that the JNK and SPHK-1, and not the p38, pathways are involved in suppressing apoptosis. This information provides evidence that EGF stimulates survival along multiple pathways that differ in trophoblast and other cell types.
Placenta 2005 Aug
PMID:Multiple anti-apoptotic pathways stimulated by EGF in cytotrophoblasts. 1599 4


1 2 3 4 5 6 Next >>