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Query: UNIPROT:P06889 (Mol)
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Recent studies suggest that ischemia activates Src and members of the mitogen-activated protein (MAP) kinase superfamily and their downstream effectors, including big MAP kinase 1 (BMK1) and p90 ribosomal S6 kinase (p90RSK). It has also been reported that adenosine is released during ischemia and involved in triggering the protective mechanism of ischemic preconditioning. To assess the roles of Src and adenosine in ischemia-induced MAP kinases activation, we utilized the Src inhibitor PP2 (4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and the adenosine receptor antagonist 8-(p-sulfophenyl) theophylline (SPT) in perfused guinea pig hearts. PP2 (1 microm) inhibited ischemia-induced Src, BMK1 and JNK activation but not JAK2 and p38 activation. SPT inhibited ischemia-mediated p38 and JNK activation. These results demonstrate that Src family kinase and adenosine regulate MAP kinases by parallel pathways. Preconditioning significantly improved both recovery of developed pressure and dp/dt in isolated guinea pig hearts. Since the protective effect of preconditioning was blocked by PP2 (1 microm) and SPT (50 microm), we next investigated the regulation of Src, MAP kinases and p90RSK during preconditioning. The activity and time course of ERK1/2 was not changed, but p90RSK activation by reperfusion was completely inhibited by preconditioning. In contrast, the activation by ischemia of Src, BMK1, p38 and JNK was significantly faster in preconditioned hearts. Maximal BMK1 activation by ischemia was also significantly enhanced by preconditioning. These data suggest important roles for Src family kinases and adenosine in mediating preconditioning, and suggest specific roles for individual MAP kinases in preconditioning.
J Mol Cell Cardiol 2001 Nov
PMID:Src family kinase and adenosine differentially regulate multiple MAP kinases in ischemic myocardium: modulation of MAP kinases activation by ischemic preconditioning. 1170 43

SDZ PSC 833 (PSC 833), a P-glycoprotein-targeted multidrug resistance modulator, sensitizes cancer cells to chemotherapy. Here we show that PSC 833 also potentiates the formation of ceramide. Because ceramide is a second messenger in chemotherapy-induced apoptosis, knowledge of the lipid pathways influenced by PSC 833 is of relevance. In intact MDA-MB 468 breast cancer cells, ceramide generation increased 3-fold 1 h after PSC 833 addition (5.0 microM). Cyclosporine A, a structural analogue, failed to impact ceramide metabolism. Sphinganine, the upstream precursor of ceramide, also increased in response to PSC 833, and this could be blocked by adding L-cycloserine, a serine palmitoyltransferase (SPT) inhibitor. Exposure of cultured cells to PSC 833 (30 min to 4 h; 1-10 microM), followed by isolation of microsomes for in vitro assay, increased SPT activity 60%, whereas palmitoyl CoA synthetase and ceramide synthase activities were not altered. SPT activity was also heightened by pretreating cells with either paclitaxel, N-(4-hydroxyphenyl)retinamide, etoposide, or daunorubicin; however, activation was half that attained by PSC 833. PSC 833 stimulated ceramide generation in other breast cancer cell lines as well, including BT-20, MDA-MB 231, Hs 578T, T-47D, and MCF-7. In summary, several types of anticancer agents and the P-glycoprotein modulator PSC 833 share the ability to increase cellular ceramide levels by activation of SPT, the rate-limiting enzyme in the de novo pathway of ceramide synthesis. These data provide novel insight in the area of lipid-mediated cell death.
Mol Cancer Ther 2002 Jul
PMID:Enhanced de novo ceramide generation through activation of serine palmitoyltransferase by the P-glycoprotein antagonist SDZ PSC 833 in breast cancer cells. 1247 68

During transcription elongation, eukaryotic RNA polymerase II (Pol II) must contend with the barrier presented by nucleosomes. The conserved Spt4-Spt5 complex has been proposed to regulate elongation through nucleosomes by Pol II. To help define the mechanism of Spt5 function, we have characterized proteins that coimmunopurify with Spt5. Among these are the general elongation factors TFIIF and TFIIS as well as Spt6 and FACT, factors thought to regulate elongation through nucleosomes. Spt5 also coimmunopurified with the mRNA capping enzyme and cap methyltransferase, and spt4 and spt5 mutations displayed genetic interactions with mutations in capping enzyme genes. Additionally, we found that spt4 and spt5 mutations lead to accumulation of unspliced pre-mRNA. Spt5 also copurified with several previously unstudied proteins; we demonstrate that one of these is encoded by a new member of the SPT gene family. Finally, by immunoprecipitating these factors we found evidence that Spt5 participates in at least three Pol II complexes. These observations provide new evidence of roles for Spt4-Spt5 in pre-mRNA processing and transcription elongation.
Mol Cell Biol 2003 Feb
PMID:Dual roles for Spt5 in pre-mRNA processing and transcription elongation revealed by identification of Spt5-associated proteins. 1255 96

In mammalian cells, the human adenovirus type 5 early region 1A (E1A) oncoprotein functions as a thyroid hormone (TH)-dependent activator of the thyroid hormone receptor (TR). Interestingly, in the cellular context of the yeast Saccharomyces cerevisiae, E1A acts as a TR-specific constitutive coactivator that is down-regulated by TH. TH reduces the interaction of E1A with the TR in yeast but not HeLa cells. The N-terminal 82 amino acids of E1A are sufficient for coactivation in yeast and residues 4-29 are essential. In yeast, expression of the nuclear receptor corepressor (N-CoR) could down-regulate constitutive transcriptional activation of the TR by E1A, whereas expression of the glucocorticoid receptor interacting protein 1 (GRIP-1) coactivator reconstituted the E1A-induced pattern of enhanced TH-dependent gene activation by TR observed in mammalian cells. We further show that the mating type switching gene (SWI)/sucrose nonfermenting (SNF) gene chromatin remodeling complex is required for both TH/GRIP-1- and E1A-dependent coactivator function, whereas the general control nonrepressed protein (GCN5)/alteration/deficiency in activation protein (ADA2) components of the SPT, ADA, GCN5, acetylation (SAGA) transcriptional adaptor complex are required for TH/GRIP-1, but not E1A-dependent activation of the TR. Taken together, these studies demonstrate that the novel TR-specific coactivator function of E1A in yeast depends on the SWI/SNF chromatin remodeling complex and can be further influenced by changes in the cellular complement of transcriptional coregulatory proteins.
Mol Endocrinol 2003 Jun
PMID:Cellular context of coregulator and adaptor proteins regulates human adenovirus 5 early region 1A-dependent gene activation by the thyroid hormone receptor. 1263 85

Eukaryotic cells have a highly conserved response to an increase in temperature, termed the heat shock response. Recent research has revealed multiple roles for various sphingolipids in the heat shock responses of both yeast and mammalian cells. Heat stressed or shocked yeast and mammalian cells have an acute activation of serine palmitoyltransferase, resulting in the de novo biosynthesis of sphingolipids. Also, both mammalian and yeast cells were shown to increase ceramide levels upon heat stress or shock. In yeast cells, several functions have emerged for the de novo produced sphingoid bases in terms of the heat stress response. These functions include a role in accumulation of trehalose, a role in the heat-induced transient G0/G1 cell cycle arrest and phytosphingosine activation of a ubiquitin protein degradation pathway. However, in mammalian systems, ceramides have been demonstrated as bioactive lipids. Ceramides produced in response to heat shock were demonstrated to induce the production of c-jun, leading to apoptosis, and to be upstream of dephosphorylation of serine-rich proteins. Increasingly, sphingolipids are emerging as bioactive signaling molecules involved in numerous aspects of the eukaryotic heat shock response.
Cell Mol Life Sci 2003 Apr
PMID:The emerging role for sphingolipids in the eukaryotic heat shock response. 1278 17

Cannabinoids have recently been shown to induce the expression of the cyclooxygenase-2 (COX-2) isoenzyme in H4 human neuroglioma cells. Using this cell line, the present study investigates the contribution of the second messenger ceramide to this signaling pathway. Incubation of cells with the endocannabinoid analog R(+)-methanandamide (R(+)-MA) was associated with an increase of intracellular ceramide levels. Enhancement of ceramide formation by R(+)-MA was abolished by fumonisin B1, a ceramide synthase inhibitor, whereas inhibitors of neutral sphingomyelinase (spiroepoxide, glutathione) and serine palmitoyltransferase (l-cycloserine, ISP-1) were inactive in this respect. R(+)-MA caused a biphasic activation of the p38 and p42/44 mitogen-activated protein kinases (MAPKs), with phosphorylation peaks occurring after 15-min and 4- to 8-h treatments, respectively. Inhibition of ceramide synthesis with fumonisin B1 was associated with a suppression of R(+)-MA-induced delayed phosphorylations of p38 and p42/44 MAPKs and subsequent COX-2 expression. The involvement of ceramide in COX-2 expression was corroborated by findings showing that C2-ceramide and neutral sphingomyelinase from Bacillus cereus caused concentration-dependent increases of COX-2 expression that were suppressed in the presence of 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)imidazol (SB203580, a p38 MAPK inhibitor) or 2'-amino-3'-methoxyflavone (PD98059, a p42/44 MAPK activation inhibitor). In contrast, dihydro-C2-ceramide being used as a negative control did not induce MAPK phosphorylation and COX-2 expression. Collectively, our results demonstrate that R(+)-MA induces COX-2 expression in human neuroglioma cells via synthesis of ceramide and subsequent activation of p38 and p42/44 MAPK pathways. Induction of COX-2 expression via ceramide represents a hitherto unknown mechanism by which cannabinoids mediate biological effects within the central nervous system.
Mol Pharmacol 2003 Nov
PMID:Ceramide is involved in r(+)-methanandamide-induced cyclooxygenase-2 expression in human neuroglioma cells. 1457 69

Sphingolipids are structural components of the eukaryotic plasma membrane that are involved, together with cholesterol, in the formation of lipid microdomains (rafts). Additionally, sphingolipid metabolites have been shown to modulate a wide variety of cellular events, including differentiation and apoptosis. To investigate the role of de novo sphingolipid biosynthesis in Leishmania, we have focused on serine palmitoyltransferase (SPT), which catalyses the first, rate-limiting step in the synthetic pathway. Genetic ablation of one SPT subunit, LmLCB2, yields viable null parasites that can no longer synthesize ceramide and sphingolipids de novo. Unexpectedly, LmLCB2 expression (and sphingolipid biosynthesis) is stage regulated in Leishmania, being undetectable in intramacrophage parasites. As expected from this observation, the LmLCB2 null mutants maintain infectivity in vivo. However, they are compromised in their ability to form infective extracellular parasites, correlating with a defect in association of the virulence factor, leishmanolysin or GP63, with lipid rafts during exocytosis and an observed relocalization of a second virulence factor, lipophosphogycan, during differentiation. Thus, de novo sphingolipid biosynthesis is critical for membrane trafficking events in extracellular Leishmania but has at best a minor role in intracellular pathogenesis.
Mol Microbiol 2004 Apr
PMID:Sphingolipid-free Leishmania are defective in membrane trafficking, differentiation and infectivity. 1506 23

Summary relatively large rafts are a feature of activated mammalian cells. These studies allow us to consider the functional role of lipid rafts in kinetoplastid parasites, which are particularly rich in lipid-anchored surface molecules. Morphological, biochemical and genetic studies indicate that lipid rafts (and sphingolipid biosythesis) are important in the differentiation of extracellular Leishmania to mammalian-infective metacyclic promastigotes, perhaps orchestrating the clearly observable reorganization of the plasma membrane during this process that leads to an activated metacyclic primed for invasion. However, the first step in the sphingolipid biosynthetic pathway (mediated by serine palmitoyltransferase), and at least regulated, de novo sphingoid base and ceramide synthesis, are not essential for the pathogenesis of intramacrophage Leishmania amastigotes.
Mol Microbiol 2004 Aug
PMID:Rafts and sphingolipid biosynthesis in the kinetoplastid parasitic protozoa. 1525 87

Dihydroceramide desaturase catalyzes the conversion of the innocuous precursor dihydroceramide into a highly bioactive product ceramide. We studied the effect of N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first inhibitor of this enzyme, in primary cultured cerebellar neurons. Although desaturase was efficiently inhibited (IC50 of 23 nM), the compound lost its specificity at higher concentrations. From 5 microM upward, GT11 also decreased de novo sphingolipid biosynthesis. Studies with two differentially labeled radioactive analogs of GT11 support that the inhibitor itself and not a downstream metabolic product, interferes with sphingolipid biosynthesis. It is interesting that serine palmitoyltransferase activity decreased in the presence of high concentrations of GT11 in intact cells, but not when added directly into cell homogenates. However, suppression of enzyme transcription could not be detected. But at high concentrations GT11 provoked an accumulation of sphingosine-1-phosphate and especially of dihydrosphingosine-1-phosphate, suggesting a decreased activity of sphingosine-1-phosphate lyase. Enzyme activity measurements indeed supported this assumption. Thus, at higher concentrations, GT11 interferes with lyase activity, inducing an accumulation of sphingoid base phosphates that, in turn, down-regulate serine palmitoyltransferase activity. At low concentrations, however, GT11 is the first specific inhibitor of dihydroceramide desaturase described so far. Considering the proapoptotic and proinflammatory effect of ceramide, GT11 could also turn out to be a novel cell-protective agent.
Mol Pharmacol 2004 Dec
PMID:Specificity of the dihydroceramide desaturase inhibitor N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11) in primary cultured cerebellar neurons. 1537 59

A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P</=0.001): 6q14 for %FEV(1), 12p13 for IgE, 17q22-q24 for SPT and 21q21 for both SPTQ and %FEV(1). Nine other regions indicated smaller linkage signals (0.001<P</=0.005). While most of these regions have been reported by previous asthma and lung function screens, 6q14 appears to be a new region potentially linked to %FEV(1). To determine which of these various asthma phenotypes are more likely to share common genetic determinants, a principal component analysis was applied to the genome-wide LOD scores. This analysis revealed clustering of LODs for asthma, SPT and Phadiatop on one axis and clustering of LODs for %FEV(1), BR and SPTQ on the other, while LODs for IgE and eosinophils appeared to be independent from all other LODs. These results provide new insights into the potential sharing of genetic determinants by asthma-related phenotypes.
Hum Mol Genet 2004 Dec 15
PMID:Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families. 1550 91


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