Search results for "Mitogen-Activated Protein Kinases"
showing 10 items of 246 documents
Apoptosis induced by (E)-5-(2-bromovinyl)-2'-deoxyuridine in varicella zoster virus thymidine kinase-expressing cells is driven by activation of c-Ju…
2003
The molecular mode of cell killing by the antiviral drug (E)-5-(2-bromovinyl-2'-deoxyuridine (BVDU) was studied in Chinese hamster ovary (CHO) cells stably transfected with the thymidine kinase gene (tk) of varicella zoster virus (CHO-VZVtk). The colony-forming ability of the cells was reduced to <1% at a concentration of approximately 1 microM BVDU, whereas for nontransfected cells or cells transfected with tk gene of herpes simplex virus type 1 (CHO-HSVtk), a 1000-fold higher dose was required to achieve the same response. BVDU inhibited thymidylate synthase in CHO-VZVtk but not in CHO-HSVtk and control cells. On the other hand, the drug was incorporated into DNA of VZVtk- and HSVtk-expre…
Tristetraprolin Regulates the Expression of the Human Inducible Nitric-Oxide Synthase Gene
2005
The expression of human inducible NO synthase (iNOS) is regulated both by transcriptional and post-transcriptional mechanisms. Stabilization of mRNAs often depends on activation of p38 mitogen-activated protein kinase (p38 MAPK). In human DLD-1 cells, inhibition of p38 MAPK by the compound 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) or by overexpression of a dominant-negative p38 MAPKalpha protein resulted in a reduction of human iNOS mRNA and protein expression, whereas human iNOS promoter activity was not affected. An important RNA binding protein regulated by the p38 MAPK pathway and involved in the regulation of the stability of several mRNAs is tr…
Protein Kinase C μ Is Regulated by the Multifunctional Chaperon Protein p32
2000
We identified the multifunctional chaperon protein p32 as a protein kinase C (PKC)-binding protein interacting with PKCalpha, PKCzeta, PKCdelta, and PKC mu. We have analyzed the interaction of PKC mu with p32 in detail, and we show here in vivo association of PKC mu, as revealed from yeast two-hybrid analysis, precipitation assays using glutathione S-transferase fusion proteins, and reciprocal coimmunoprecipitation. In SKW 6.4 cells, PKC mu is constitutively associated with p32 at mitochondrial membranes, evident from colocalization with cytochrome c. p32 interacts with PKC mu in a compartment-specific manner, as it can be coimmunoprecipitated mainly from the particulate and not from the so…
Design and synthesis of 1-aryl-5-anilinoindazoles as c-Jun N-terminal kinase inhibitors.
2012
Starting from pyrazole HTS hit (1), a series of 1-aryl-1H-indazoles have been synthesized as JNK3 inhibitors with moderate selectivity against JNK1. SAR studies led to the synthesis of 5r as double digital nanomolar JNK3 inhibitor with good in vivo exposure.
Diacylglycerols containing Omega 3 and Omega 6 fatty acids bind to RasGRP and modulate MAP kinase activation.
2003
We elucidated the effects of different diacylglycerols (DAGs), i.e. 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG), 1-stearoyl-2-docosahexaenoyl-sn-glycerol (SDG), and 1-stearoyl-2-eicosapentaenoyl-sn-glycerol (SEG), on [3H]PDBu binding to RasGRP. The competition studies with these DAGs on [3H]PDBu binding to RasGRP revealed different Ki values for these DAG molecular species. Furthermore, we transfected human Jurkat T cells by a plasmid containing RasGRP and assessed the implication of endogenous DAGs on activation of MAP kinases ERK1/ERK2, induced by phorbol-12-myristate-13-acetate (PMA). In control cells, GF109203X, a protein kinase C inhibitor, inhibited ERK1/ERK2 activation. However, this…
Cross-talk between oxidative stress and pro-inflammatory cytokines in acute pancreatitis: a key role for protein phosphatases.
2009
Acute pancreatitis is an acute inflammatory process localized in the pancreatic gland that frequently involves peripancreatic tissues. It is still under investigation why an episode of acute pancreatitis remains mild affecting only the pancreas or progresses to a severe form leading to multiple organ failure and death. Proinflammatory cytokines and oxidative stress play a pivotal role in the early pathophysiological events of the disease. Cytokines such as interleukin 1beta and tumor necrosis factor alpha initiate and propagate almost all consequences of the systemic inflammatory response syndrome. On the other hand, depletion of pancreatic glutathione is an early hallmark of acute pancreat…
The collagen receptor integrins have distinct ligand recognition and signaling functions
2000
Distinct collagen subtypes are recognized by specific cell surface receptors. Two of the best known collagen receptors are members of the integrin family and are named alpha1beta1 and alpha2beta1. Integrin alpha1beta1 is abundant on smooth muscle cells, whereas the alpha2beta1 integrin is the major collagen receptor on epithelial cells and platelets. Many cell types, such as fibroblasts, osteoblasts, chondrocytes, endothelial cells, and lymphocytes may concomitantly express both of the receptors. We have studied the cell biology of these integrins at two levels. First, we have analyzed their ligand binding mechanism and specificity. Second, we have studied their signaling function inside th…
Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and glycogen synthase kinase 3 beta.
2002
The integrins are a large family of heterodimeric transmembrane receptors composed of α and β subunits (22). In addition to mediating cell-matrix interactions, integrins have been shown to activate intracellular signaling pathways which, in collaboration with growth factor-induced signals, regulate cellular functions (46). Some integrin signaling cascades are activated via the β subunit cytoplasmic domain, and they are therefore triggered by several integrin heterodimers. These signals include the activation of protein tyrosine kinases of the Src and focal adhesion kinase (FAK) families (9, 47). More-recent studies have revealed signaling events that are activated specifically by an α subun…
Differential role of p38 mitogen activated protein kinase for cellular recovery from attack by pore-forming S. aureus alpha-toxin or streptolysin O.
2006
Following the observation that cells are able to recover from membrane lesions incurred by Staphylococcus aureus alpha-toxin and streptolysin O (SLO), we investigated the role of p38 in this process. p38 phosphorylation occurred in response to attack by both toxins, commencing within minutes after toxin treatment and waning after several hours. While SLO reportedly activates p38 via ASK1 and ROS, we show that this pathway does not play a major role for p38 induction in alpha-toxin-treated cells. Strikingly divergent effects of p38 blockade were noted depending on the toxin employed. In the case of alpha-toxin, inhibition of p38 within the time frame of its activation led to disruption of th…
Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity
2013
Jak/Tyk proteins have recently aroused as possible therapeutic targets for the treatment of psoriasis. In psoriasis, these proteins signal through STAT molecules including STAT3, and STAT3 expression and activation has been shown augmented in psoriatic lesions. Here, we characterized the expression of Jak/Tyk proteins in lesional compared with non-lesional psoriatic skin. Jak1, Jak2 mRNA and protein and Tyk2 mRNA appeared to be downregulated, whereas Jak3 mRNA expression was increased. Moreover, STAT3 expression and activation was examined in psoriasis. STAT3 is activated at two phosphorylation sites: Tyr705 and Ser727. Both phosphorylation sites were phosphorylated in lesional psoriatic sk…