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At least 361 records · Page 20Linked to original sources
PubMed2005

Endocytic pathway for surfactant protein A in human macrophages: binding, clathrin-mediated uptake, and trafficking through the endolysosomal pathway.

In the noninflamed lung, surfactant protein A (SP-A) acts as an anti-inflammatory molecule through its effects on macrophage (MPhi) function, modulating cytokine and reactive oxygen and nitrogen intermediate production. The receptors responsible for these effects of SP-A on human MPhi are not clear, although SP-A binding to several proteins has been described. In this study, we demonstrate high-affinity specific binding of SP-A to primary human MPhi. SP-A binding was inhibited by EGTA, indicating calcium dependence. However, mannan did not inhibit SP-A binding, suggesting that binding is mediated by a direct protein-protein interaction that does not involve carbohydrate recognition. Our laboratory has previously shown that SP-A is rapidly endocytosed by human MPhi into discrete vesicles. Although previous work indicates that SP-A is ultimately degraded by murine MPhi over time, the trafficking pathway of SP-A through MPhi after uptake has not been reported and is of potential biological importance. We examined trafficking of SP-A in human MPhi by electron and confocal microscopy and show for the first time that SP-A is endocytosed by primary human MPhi through clathrin-coated pits and colocalizes sequentially over time with the early endosome marker EEA1, late endosome marker lamp-1, and lysosome marker cathepsin D. We conclude that SP-A binds to receptor(s) on human MPhi, is endocytosed by a receptor-mediated, clathrin-dependent process, and trafficks through the endolysosomal pathway. These studies provide further insight into the interactions of SP-A with the MPhi cell surface and intracellular compartments that play important roles in SP-A modulation of lung MPhi biology.

Calcium↗
PubMed2004

Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth.

We describe a novel approach that allows detection of primary and metastatic cells in vivo in which either the extracellular signal-regulated kinase (ERK) or the p38 pathway is activated. Our recent findings showed that ERK and p38 kinases regulate, respectively, programs dictating cell proliferation (high ERK-to-p38 ratio) or growth arrest and dormancy (low ERK-to-p38 ratio) in vivo. Thus, we were able to use green fluorescent protein (GFP) to reflect ERK and p38 activities and, consequently, the proliferative state of cancer cells. This was accomplished by transfecting tumorigenic T-HEp3 and HT1080 cells, and dormant D-HEp3 cells, with plasmids coding for Elk-GAL4 or CHOP-GAL4 fusion proteins that, when phosphorylated by either ERK or p38, respectively, transactivated a GFP-reporter gene. The fate of these cells was examined in culture, in primary sites, and in spontaneous metastasis in chick embryos and nude mice. In culture GFP level was directly proportional to the previously established levels of ERK or p38 activation. In contrast, during the first 24 hours of in vivo inoculation, both the tumorigenic and the dormant cells strongly activated the p38 pathway. However, in the tumorigenic cells, p38 activity was rapidly silenced, correcting the ERK/p38 imbalance and contributing to high ERK activity throughout the entire period of tumor growth. In contrast, in the small nodules formed by dormant cells, the level of ERK activity was dramatically reduced, whereas p38 activity remained high. Strong activation of ERK was evident in metastatic sites, whereas p38 activation was silenced in this anatomic location as well. These results show that it is possible to directly measure cancer cell response to microenvironment with this reporter system and that only proliferation-competent cells have the ability to rapidly adapt ERK and p38 signaling for proliferative success. This approach allows isolation and further characterization of metastatic cells with specific signaling signatures indicative of their phenotypes.

Animals↗
PubMed2003

MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival.

The mitogen-activated protein kinase (MAPK) (also called extracellular signal-regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia-1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor-related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappabeta (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.

Antineoplastic Agents↗
PubMed2002

Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway.

Platelet factor 4 (PF-4) is a member of the chemokine family with powerful antiangiogenic properties. The mechanism by which PF-4 inhibits endothelial cell proliferation is unclear. We investigated the effects of PF-4 on the intracellular signal transduction induced by basic fibroblast growth factor (FGF2). We found that PF-4 (10 microg/mL) inhibited the FGF2-induced proliferation of adrenal cortex capillary endothelial (ACE) cells. The inhibition of MEK1/2 (mitogen-activated protein kinase kinase) by PD98059 or of PI3K (phosphatidylinositol 3-kinase) by Ly294002 abolished the proliferation induced by FGF2, suggesting that ACE cell proliferation required dual signaling through both the extracellular signal-regulated kinase (ERK) and PI3K pathways. Ly294002 had no significant effect on ERK phosphorylation, whereas PD98059 had a weak effect on the phosphorylation of Akt, suggesting that 2 separate cascades are required for ACE cell proliferation. The addition of PF-4 (10 microg/mL) significantly inhibited ERK phosphorylation (95%), showing that PF-4 acted directly on or upstream from this kinase. Surprisingly, PF-4 did not affect FGF2-induced Akt phosphorylation. This suggests that PF-4 disrupts FGF2 signaling via an intracellular mechanism of inhibition. To exclude the possibility that PF-4 inhibited the binding of FGF2 to only one FGF receptor, preferentially activating the ERK pathway, we investigated the effect of PF-4 on FGF2-induced ERK and Akt phosphorylation, using mutant heparan sulfate-deficient Chinese hamster ovary cells transfected with the FGF-R1 cDNA. The addition of PF-4 (1 microg/mL) significantly inhibited ERK phosphorylation (90%), with no effect on Akt phosphorylation, suggesting that PF-4 acts downstream from the FGF-R1 receptor. In conclusion, this is the first report showing that PF-4 inhibits FGF2 activity downstream from its receptor.

Adrenal Cortex↗
PubMed2002

The role of the ubiquitination-proteasome pathway in breast cancer: applying drugs that affect the ubiquitin-proteasome pathway to the therapy of breast cancer.

The ubiquitin-proteasome pathway is responsible for most eukaryotic intracellular protein degradation. This pathway has been validated as a target for antineoplastic therapy using both in vitro and preclinical models of human malignancies, and is influenced as part of the mechanism of action of certain chemotherapeutic agents. Drugs whose primary action involves modulation of ubiquitin-proteasome activity, most notably the proteasome inhibitor PS-341, are currently being evaluated in clinical trials, and have already been found to have significant antitumor efficacy. On the basis of the known mechanisms by which these agents work, and the available clinical data, they would seem to be well suited for the treatment of breast neoplasms. Such drugs, alone and especially in combination with current chemotherapeutics, may well represent important advances in the therapy of patients with breast cancer.

Antineoplastic Agents↗
PubMed2004

Breast cancer oestrogen independence mediated by BCAR1 or BCAR3 genes is transmitted through mechanisms distinct from the oestrogen receptor signalling pathway or the epidermal growth factor receptor signalling pathway.

INTRODUCTION: Tamoxifen is effective for endocrine treatment of oestrogen receptor-positive breast cancers but ultimately fails due to the development of resistance. A functional screen in human breast cancer cells identified two BCAR genes causing oestrogen-independent proliferation. The BCAR1 and BCAR3 genes both encode components of intracellular signal transduction, but their direct effect on breast cancer cell proliferation is not known. The aim of this study was to investigate the growth control mediated by these BCAR genes by gene expression profiling. METHODS: We have measured the expression changes induced by overexpression of the BCAR1 or BCAR3 gene in ZR-75-1 cells and have made direct comparisons with the expression changes after cell stimulation with oestrogen or epidermal growth factor (EGF). A comparison with published gene expression data of cell models and breast tumours is made. RESULTS: Relatively few changes in gene expression were detected in the BCAR-transfected cells, in comparison with the extensive and distinct differences in gene expression induced by oestrogen or EGF. Both BCAR1 and BCAR3 regulate discrete sets of genes in these ZR-75-1-derived cells, indicating that the proliferation signalling proceeds along distinct pathways. Oestrogen-regulated genes in our cell model showed general concordance with reported data of cell models and gene expression association with oestrogen receptor status of breast tumours. CONCLUSIONS: The direct comparison of the expression profiles of BCAR transfectants and oestrogen or EGF-stimulated cells strongly suggests that anti-oestrogen-resistant cell proliferation is not caused by alternative activation of the oestrogen receptor or by the epidermal growth factor receptor signalling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The cell adhesion molecule Echinoid defines a new pathway that antagonizes the Drosophila EGF receptor signaling pathway.

Photoreceptor and cone cells in the Drosophila eye are recruited following activation of the epidermal growth factor receptor (EGFR) pathway. We have identified echinoid (ed) as a novel putative cell adhesion molecule that negatively regulates EGFR signaling. The ed mutant phenotype is associated with extra photoreceptor and cone cells. Conversely, ectopic expression of ed in the eye leads to a reduction in the number of photoreceptor cells. ed expression is independent of EGFR signaling and ED is localized to the plasma membrane of every cells throughout the eye disc. We present evidence that ed acts nonautonomously to generate extra R7 cells by a mechanism that is sina-independent but upstream of Tramtrack (TTK88). Together, our results support a model whereby ED defines an independent pathway that antagonizes EGFR signaling by regulating the activity, but not the level, of the TTK88 transcriptional repressor.

Alleles↗
PubMed1996

Selective slow pathway ablation in atrioventricular nodal reentrant tachycardia--comparison of different methods and the site of slow pathway ablation.

The optimum potential of the slow pathway (SP) was investigated by determining the effectiveness and safety of high-radiofrequency catheter ablation to treat atrioventricular nodal reentrant tachycardia (AVNRT). The subjects consisted of 29 patients with AVNRT (11 men, with a mean age of 54 +/- 15 years). Three ablation methods were used: a) Method A used the earliest atrial activation site, which is retrograde to the slow pathway, b) Method SP used the SP potential, and c) Method SW, in which ablation was performed stepwise starting from the coronary sinus and moving toward the recording site of the His bundle potential. Five, 20, and 4 patients underwent Methods A, SP, and SW, respectively. The fewest number of applications was needed with Method SP (11 +/- 9, 6 +/- 4, and 13 +/- 9), and the delivered energy was also lowest with Method SP (9151 +/- 6119, 3712 +/- 2168, and 12183 +/- 4090 J, with Methods A, SP, and SW, respectively). In Method SP, the interval between the atrium and SP was significantly longer at sites which cured tachycardia, than at sites at which ablation was ineffective (88 +/- 26 vs 66 +/- 22 msec, p < 0.05). The SP potential showed a humped shape in 18 of 20 patients. Method SP was the most efficient ablation method for treating AVNRT.

Adult↗
PubMedDate not supplied

NaF induces early differentiation of murine bone marrow cells along the granulocytic pathway but not the monocytic or preosteoclastic pathway in vitro.

The stimulatory effects of sodium fluoride (NaF) on bone formation have been explained solely by its activation of osteoblasts. However, whether and how NaF acts on the osteoclast lineage is poorly understood. We previously found that NaF differentiates HL-60 cells to granulocytic cells. To further test this action, we have employed here primary cultures of progenitor cells derived from murine bone marrow. NaF at subtoxic concentrations (<0.5 mM) significantly up-regulated activities of several intracellular enzymes (lactate dehydrogenase, beta-glucuronidase, acid phosphatase), cellular reduction of nitroblue tetrazolium, and nitric oxide (NO) production; which are all accepted as general differentiation markers. NaF (<0.5 mM) also up-regulated granulocyte-specific markers (chloroacetate esterase, cell surface antigens [Mac-1, Gr-1]) but not any of the monocyte-specific markers (nonspecific esterase, cell surface antigens [F4/80, MOMA-2]). Although other general differentiation markers (phagocytosis, adhesion, appearance, nuclear:cytoplasmic ratio) were not appreciably influenced by NaF, essentially in support of our previous data from HL-60 cells, the present findings suggest that NaF induces early differentiation of bone marrow hemopoietic progenitor cells along the granulocytic pathway but not the monocytic pathway that is linked to osteoclast formation. Therefore, in addition to its potent stimulatory effects on osteoblastic bone formation, NaF applied to patients with osteoporosis could be expected to indirectly reduce osteoclastic bone resorption.

Acid Phosphatase↗
PubMed1994

Radiofrequency ablation for the fast pathway of atrioventricular node reentry. Evidence for partial damage to the fast and lower common pathways.

Radiofrequency ablation was attempted in a 30-year-old woman with atrioventricular (AV) node reentry of the common variety. Energy was delivered to ablate a fast pathway. After energy delivery, the atrio-His interval prolonged following transient AV node block. Retrograde conduction was no longer present. However, dual AV nodal physiology and AV node reentry with similar retrograde atrial activation sequence could be shown post-ablation. These observations suggest that both fast and lower common pathways were partially damaged by ablation.

Adult↗
PubMed1991

Investigations on the metabolic pathways of cyclosporine: II. Elucidation of the metabolic pathways in vitro by human liver microsomes.

1. Cyclosporine and its metabolites, isolated from human bile and identified by FAB mass spectrometry and 1H-n.m.r. spectroscopy, were metabolized by human liver microsomes for the identification of new cyclosporine metabolites. From these data a metabolic pathway for cyclosporine, which includes these new cyclosporine metabolites, has been proposed. The new metabolites were isolated by semi-preparative h.p.l.c. and their chemical structures were elucidated by FAB mass spectrometry. These isolated metabolites were further metabolized and the products identified by FAB mass spectrometry. 2. Fourteen metabolites, whose structure has not yet been elucidated, were isolated after metabolism of structurally identified cyclosporine metabolites, and chemical structures for five of these metabolites were proposed. 3. The structures of the new cyclosporine metabolites were: (i) a N-demethylated, carboxylated derivative (AM1A4N), (ii) a di-hydroxylated, N-demethylated derivative (AM14N9), (iii) a hydroxylated and carboxylated derivative (AM1A9), (iv) a di-hydroxylated, cyclized and N-demethylated derivative (AM1c4N9) and (v) a cyclized and carboxylated (AM1cA) derivative. 4. A proposed cyclosporine metabolic pathway comprises a total of 29 metabolites. It consists of four main branches originating from metabolites AM1, AM1c, AM9 and AM4N.

Bile↗
PubMed2000

The Agrin/MuSK signaling pathway is spatially segregated from the neuregulin/ErbB receptor signaling pathway at the neuromuscular junction.

The neuregulin/erbB receptor and agrin/MuSK pathways are critical for communication between the nerve, muscle, and Schwann cell that establishes the precise topological arrangement at the vertebrate neuromuscular junction (NMJ). ErbB2, erbB3, and erbB4 as well as neuregulin, agrin, and MuSK are known to be concentrated at the NMJ. Here we have examined NMJs from gastrocnemius muscle of adult rat using immunofluorescence confocal microscopy to characterize in detail the distribution of these proteins relative to the distribution of acetylcholine receptors (AChRs). We have determined that erbB2 and erbB4 are enriched in the depths of the secondary junctional folds on the postsynaptic muscle membrane. In contrast, erbB3 at the NMJ was concentrated at presynaptic terminal Schwann cells. This distribution strongly argues that erbB2/erbB4 heterodimers are the functional postsynaptic neuregulin receptors of the NMJ. Neuregulin was localized to the axon terminal, secondary folds, and terminal Schwann cells, where it was in a position to signal through erbB receptors. MuSK was concentrated in the postsynaptic primary gutter region where it was codistributed with AChRs. Agrin was present at the axon terminal and in the basal lamina associated with the primary gutter region, but not in the secondary junctional folds. The differential distributions of the neuregulin and agrin signaling pathways argue against neuregulin and erbB receptors being localized to the NMJ via direct interactions with either agrin or MuSK.

Agrin↗
PubMed2001

The MEK1-ERK map kinase pathway and the PI 3-kinase-Akt pathway independently mediate anti-apoptotic signals in HepG2 liver cancer cells.

Primary liver cancers, which are generally hypervascular in nature, depend highly on blood supply. So far there are few reports on apoptosis of liver cancer cells upon deprivation of serum-derived survival factors. The aim of our study is to clarify molecular mechanisms by which liver cancer cells survive with the aid of serum. In HepG2 liver cancer cells, serum deprivation induced time-dependent increase in the number of apoptotic cells, which was detected by fragmentation of genomic DNA and fluorescent nuclear staining. The activity of extracellular signal-regulated kinase (ERK) did not decrease considerably after serum deprivation, although it increased after serum stimulation. However, we found that the MEK1 inhibitor PD98059, but not the p38 kinase inhibitor SB203580, potently induced apoptosis of the liver cancer cells in the presence of serum, indicating that the MEK-ERK signaling pathway is required for serum-dependent survival of HepG2 cells. In agreement with this notion, transient expression of active MEK1 prevented apoptosis in serum-deprived condition. We also found that the protective effect of serum against apoptosis was totally abrogated by LY294002 or wortmannin, which are the inhibitors of phosphatidylinositol (PI) 3-kinase. The activity of Akt, the target of PI 3-kinase, decreased gradually after deprivation of serum, whereas it was rapidly reactivated upon serum stimulation. These data indicate that survival of HepG2 liver cancer cells depends upon serum and that both the MEK1-ERK- and the PI 3-kinase-Akt- pathways are required for survival signaling to the nucleus.

Apoptosis↗
PubMed1991

[Right accessory pathway simulating a nodo-ventricular pathway: an electrophysiologic study and intraoperative mapping].

We report a case of a patient with episodes of wide QRS tachycardia and syncope. During the electrophysiologic study, a wide QRS tachycardia (200 b/m) with left bundle branch block morphology was reproducibly induced by incremental atrial pacing with progressive shortening of the HV interval and lengthening of the AV interval, suggesting the presence of a nodoventricular accessory pathway (Mahaim fiber). The intraoperative mapping performed during tachycardia showed the earliest ventricular activation to be over the right antero-lateral AV groove, different from the usual epicardial activation previously described. According to the earliest epicardial breakthrough point, we performed an epicardial AV fat pad dissection which produced irreversible disappearance of preexcitation, confirmed at the postoperative electrophysiologic study. No recurrence of tachycardia was observed during a follow-up of 11 months. This case further confirms previous data that the "so-called" Mahaim fibers could be a right accessory pathway with decremental properties.

Adult↗
PubMed1987

Analysis of two distinct B cell activation pathways mediated by a monoclonal T helper cell. I. MHC-restricted activation of B cells by an IL 2-dependent pathway.

The present study was carried out to determine whether the MHC-restricted and MHC-unrestricted B cell activation pathways mediated by a single cloned Th cell are separable, and whether these two pathways are mediated by distinct mechanisms. It was demonstrated that the two B cell activating functions of a single cloned Th cell could be separated by their sensitivity to irradiation. It was shown that MHC-restricted B cell activation is mediated by a radiosensitive Th cell function, whereas MHC-unrestricted B cell activation is mediated by a radioresistant function of the same Th cell. In addition, it was shown that recombinant IL 2 can restore or replace the radiosensitive component of MHC-restricted cognate helper function.

Animals↗
PubMed1977

Haemolytic assays in agarose plates for components of the classical complement pathway: interference by the alternative pathway.

It has been observed that when serum C6 is measured by the haemolytic radial diffusion technique a heat labile factor limits the size of the haemolytic rings. This reduction is haemolysis has been shown to be due to alternative pathway activation of C6 in the agarose plate; and that the heat labile factor is Factor B of the alternative pathway. This phenomenon is of practical importance when assaying for C6; however, it does not explain the observations of a C6 inactivator reported by Nelson & Biro (1968).

Antigen-Antibody Complex↗
PubMed1980

Effect of the 5-hydroperoxide of eicosatetraenoic acid and inhibitors of the lipoxygenase pathway on the formation of slow reacting substance by rat basophilic leukemia cells; direct evidence that slow reacting substance is a product of the lipoxygenase pathway.

Previous studies in a line of rat basophilic leukemia (RBL 1) cells have indicated that the slow reacting substance (SRS) made during stimulation with the divalent cation ionophore, A23187, is derived from arachidonic acid (AA). In the present report, various inhibitors of AA metabolism were compared with regard to their effects on SRS formation and incorporation of radioactivity from [1-14C]-AA into known metabolites of the lipoxygenase and cyclooxygenase pathways. An apparently close parallel between lipoxygenase product formation and SRS synthesis is demonstrated. In addition, exogenous 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) has been shown to markedly enhance SRS synthesis, even when A23187 is absent. The data provide very strong evidence that SRS is produced through the lipoxygenase pathway.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1981

[Electrophysiologic demonstration of dual atrioventricular nodal pathways and final common pathway in a case of A-V nodal paroxysmal tachycardia. Considerations on the functional complexity of the A-V node (author's transl)].

The AA. studied the A-V nodal conduction using the technique of induced PAB in a patient with A-V reentrant paroxysmal tachycardia. They observed that the conduction through the A-V node failed when coupling intervals A1-A2 were between 280 and 260 msec and, after, recovered, with consistent slackening, when A1-A2 intervals were shortened, until the atrial ERP was reached. This uncommon response indicates the functional complexity of the A-V node and, particularly, suggests the presence of a final common pathway distal to the fast and slow A-V pathways, that are the anatomic-functional basis of the reentry circuit in A-V nodal paroxismal tachycardia.

Atrioventricular Node↗