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Mitogen-activated Protein Kinase Signalling Pathway (mitogen-activated + protein_kinase_signalling_pathway)
Selected AbstractsRNA interference targeting the platelet-derived growth factor receptor , subunit ameliorates experimental hepatic fibrosis in ratsLIVER INTERNATIONAL, Issue 10 2008Si-Wen Chen Abstract Background/Aims: Platelet-derived growth factor (PDGF) is the strongest stimulator of the proliferation of hepatic stellate cells (HSCs). PDGF receptor , subunit (PDGFR-,) is acquired on HSCs proliferation induced by PDGF. In this study, we aim to investigate the effect of PDGFR-, small interference RNA (siRNA) on experimental hepatic fibrosis. Methods: We constructed a PDGFR-, siRNA expression plasmid and investigated its effect on the activation of HSCs. Bromodeoxyuridine incorporation was performed to investigate the effect of PDGFR-, siRNA on HSCs proliferation. A hydrodynamics-based transfection method was used to deliver PDGFR-, siRNA to rats with hepatic fibrosis. The distribution of transgenes in the liver was observed by immunofluorescence. The antifibrogenic effect of PDGFR-, siRNA was investigated pathologically. Results: Platelet-derived growth factor receptor-, subunit siRNA could significantly downregulate PDGFR-, expression, suppress HSCs activation, block the mitogen-activated protein kinase signalling pathway and inhibit HSCs proliferation in vitro. PDGFR-, siRNA expression plasmid could be delivered into activated HSCs by the hydrodynamics-based transfection method, and remarkably improve the liver function of the rat model induced by dimethylnitrosamine and bile duct ligation. Furthermore, the progression of fibrosis in the liver was significantly suppressed by PDGFR-, siRNA in both animal models. Conclusions: Platelet-derived growth factor receptor-, subunit siRNA may be presented as an effective antifibrogenic gene therapeutic method for hepatic fibrosis. [source] Structural analysis of an MK2,inhibitor complex: insight into the regulation of the secondary structure of the Gly-rich loop by TEI-I01800ACTA CRYSTALLOGRAPHICA SECTION D, Issue 1 2010Aiko Fujino Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK2) is a Ser/Thr kinase from the p38 mitogen-activated protein kinase signalling pathway and plays an important role in inflammatory diseases. The crystal structure of the complex of human MK2 (residues 41,364) with the potent MK2 inhibitor TEI-I01800 (pKi = 6.9) was determined at 2.9,Å resolution. The MK2 structure in the MK2,TEI-I01800 complex is composed of two domains, as observed for other Ser/Thr kinases; however, the Gly-rich loop in the N-terminal domain forms an ,-helix structure and not a ,-sheet. TEI-I01800 binds to the ATP-binding site as well as near the substrate-binding site of MK2. Both TEI-I01800 molecules have a nonplanar conformation that differs from those of other MK2 inhibitors deposited in the Protein Data Bank. The MK2,TEI-I01800 complex structure is the first active MK2 with an ,-helical Gly-rich loop and TEI-I01800 regulates the secondary structure of the Gly-rich loop. [source] Trophic factors attenuate nitric oxide mediated neuronal and axonal injury in vitro: roles and interactions of mitogen-activated protein kinase signalling pathwaysJOURNAL OF NEUROCHEMISTRY, Issue 6 2005Alastair Wilkins Abstract Inflammation in the central nervous system occurs in diseases such as multiple sclerosis and leads to axon dysfunction and destruction. Both in vitro and in vivo observations have suggested an important role for nitric oxide (NO) in mediating inflammatory axonopathy. The purposes of this study were to model inflammatory axonopathy in vitro and identify modulators of the process. Rat cortical neurones were cultured and exposed to an NO-donor plus potential protective factors. Cultures were then assessed for neuronal survival, axon survival and markers of intracellular signalling pathways. The NO-donor produced dose-dependent neuronal loss and a large degree of axon destruction. Oligodendrocyte conditioned medium (OCM) and insulin-like growth factor type-1 (IGF-1), but not glial cell line-derived neurotrophic factor (GDNF), improved survival of neurones exposed to NO donors. In addition p38 MAP kinase was activated by NO exposure and inhibition of p38 signalling led to neuronal and axonal survival effects. OCM and IGF-1 (but not GDNF) reduced p38 activation in NO-exposed cortical neurones. OCM, IGF-1 and GDNF improved axon survival in cultures exposed to NO, a process dependent on mitogen-activated protein kinase/extracellular signal-related kinase signalling. This study emphasizes that different mechanisms may underlie neuronal/axonal destructive processes, and suggests that trophic factors may modulate NO-mediated neurone/axon destruction via specific pathways. [source] Isothiocyanate E-4IB induces MAPK activation, delayed cell cycle transition and apoptosisCELL PROLIFERATION, Issue 3 2007J. Bodo Methods and results: In the current investigation, we examined the consequence of activating of signalling pathways during the release the cells from the block at G1/S boundary by synthetic isothiocyanate E-4IB. Using synchronized leukaemic HL60 cells, we show that activation of mitogen-activated protein kinases ERK1/2, c-Jun N-terminal kinase and p38 signalling pathways by E-4IB are coupled with delayed transition through the cell cycle and rapid cell cycle arrest resulted in diminished mitochondrial membrane potential culminating in apoptosis. These events were accompanied by histone deacetylase inhibition, increase of double strand DNA breaks detected by histone H2AX phosphorylation and up-regulation of cell cycle regulatory protein p21 and phosphorylation of CDC25C phosphatase. Conclusion: These findings suggest that the activation of mitogen-activated protein kinases signalling pathways, followed by the induction cell cycle arrest and apoptosis, might be responsible for anticancer activities of E-4IB. [source] | ||||||||||