Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Signaling Pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 523 records · Page 29Linked to original sources
PubMed2006

Simultaneous induction of apoptotic and survival signaling pathways in macrophage-like THP-1 cells by Shiga toxin 1.

Shiga toxins have been shown to induce apoptosis in many cell types. However, Shiga toxin 1 (Stx1) induced only limited apoptosis of macrophage-like THP-1 cells in vitro. The mechanisms regulating macrophage death or survival following toxin challenge are unknown. Differentiated THP-1 cells expressed tumor necrosis factor receptors and membrane-associated tumor necrosis factor alpha (TNF-alpha) and produced soluble TNF-alpha after exposure to Stx1. However, the cells were refractory to apoptosis induced by TNF-alpha, although the cytokine modestly increased apoptosis in the presence of Stx1. Despite the partial resistance of macrophage-like THP-1 cells to Stx1-mediated killing, treatment of these cells with Stx1 activated a broad array of caspases, disrupted the mitochondrial membrane potential (DeltaPsi(m)), and released cytochrome c into the cytoplasm. The DeltaPsi(m) values were greatest in cells that had detached from plastic surfaces. Specific caspase inhibitors revealed that caspase-3, caspase-6, caspase-8, and caspase-9 were primarily involved in apoptosis induction. The antiapoptotic factors involved in macrophage survival following toxin challenge include inhibitors of apoptosis proteins and X-linked inhibitor of apoptosis protein. NF-kappaB and JNK mitogen-activated protein kinases (MAPKs) appeared to activate survival pathways, while p38 MAPK was involved in proapoptotic signaling. The JNK and p38 MAPKs were shown to be upstream signaling pathways which may regulate caspase activation. Finally, the protein synthesis inhibitors Stx1 and anisomycin triggered limited apoptosis and prolonged JNK and p38 MAPK activation, while macrophage-like cells treated with cycloheximide remained viable and showed transient activation of MAPKs. Collectively, these data suggest that Stx1 activates both apoptotic and cell survival signaling pathways in macrophage-like THP-1 cells.

Apoptosis↗
PubMed2001

Coupling of inflammatory cytokine signaling pathways probed by measurements of extracellular acidification rate.

There is a growing interest in the mechanisms of how cells integrate the multitude of signals that emanate during inflammatory stimuli, such as the hepatic acute phase response to burn or trauma. We have used measurements of extracellular acidification rate (ECAR) of HepG2 cells cultured on microporous membranes to probe the coupling between signaling pathways for gp130 family cytokines (interleukin-6, oncostatin M) and IL-1, each of which is considered to play a significant role in the hepatic acute phase response. We found that brief (30 min or less) exposure to any of these cytokines desensitized the HepG2 cells to subsequent exposure with the same cytokine. Furthermore, we found that this property serves as a probe of the coupling of signaling pathways: exposure to IL-1 did not desensitize the cells to exposure to OSM and vice versa. However, cells exposed to IL-6 with soluble gp80, which together share with OSM the use of gp130 as a signal transducing receptor, were subsequently unable to respond to OSM, and vice versa. Simultaneous exposure of cells to moderate concentrations (near their respective EC50 values) of both IL-1 and OSM resulted in synergistic effects on the ECAR, but simultaneous exposure to saturating concentrations of IL-1 and OSM resulted in a response that tracked that of OSM alone. These results suggest that the signaling pathways of IL-1 and OSM may be simultaneously activated in HepG2 cells under moderate inflammatory cytokine challenge but that the cells must prioritize their response under extreme cytokine challenges.

Acids↗
PubMed2006

Interaction between signalling pathways involved in skeletal muscle responses to endurance exercise.

The purpose of this review is to summarise the latest literature on the signalling pathways involved in transcriptional modulations of genes that encode contractile and metabolic proteins in response to endurance exercise. A special attention has been paid to the cooperation between signalling pathways and coordinated expression of protein families that establish myofibre phenotype. Calcium acts as a second messenger in skeletal muscle during exercise, conveying neuromuscular activity into changes in the transcription of specific genes. Three main calcium-triggered regulatory pathways acting through calcineurin, Ca(2+)-calmodulin-dependent protein kinases (CaMK) and Ca(2+)-dependent protein kinase C, transduce alterations in cytosolic calcium concentration to target genes. Calcineurin signalling, the most important of these Ca(2+)-dependent pathways, stimulates the activation of many slow-fibre gene expression, including genes encoding proteins involved in contractile process, Ca(2+) uptake and energy metabolism. It involves the interaction between multiple transcription factors and the collaboration of other Ca(2+)-dependent CaMKs. Although members of mitogen-activated protein kinase (MAPK) pathways are activated during exercise, their integration into other signalling pathways remains largely unknown. The peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1alpha (PGC-1alpha) constitutes a pivotal factor of the circuitry which coordinates mitochondrial biogenesis and which couples to the expression of contractile and metabolic genes with prolonged exercise.

Exercise↗
PubMed2001

Pivotal role of the interstitial cells of Cajal in the nitric oxide signaling pathway of rat small intestine. Morphological evidence.

The nitric oxide (NO) signaling pathway is a major nonadrenergic-noncholinergic transmitter mechanism in the enteric nervous system. Our aim was to localize the enzymes in question, i.e., neuronal nitric oxide synthase (nNOS), soluble guanylate cyclase (sGC), and cGMP-dependent kinase type I (cGK-I) in rat small intestine by indirect immunofluorescence. nNOS staining was found in neurons of the myenteric plexus and in varicose nerve fibers mainly in the circular muscle layer. The cells positive for neurokinin-1 (NK-1) receptor and c-kit (interstitial cells of Cajal, ICC) in the deep muscular plexus (DMP) did not show nNOS reactivity, but nNOS-positive nerve fibers were directly adjacent to them. sGC was found in flattened cells surrounding myenteric ganglia (periganglionic cells, PGC), in ICC of the DMP, faintly in smooth muscle cells (SMC), and in cells perivascularly scattered throughout the circular muscle layer. cGK-I immunoreactivity was found abundantly in PGC (which presumably are ICC), in ICC of DMP, in SMC of the innermost circular and longitudinal muscle layers, but less intensively in the outer circular layer. Weak cGK-I staining occurred in nerve cells within the myenteric and submucosal plexus. Conclusively the key enzymes of the NO signaling pathway are differentially distributed: Occurrence of nNOS exclusively in neurons and the presence of sGC and cGK-I predominantly in ICC suggest a sequence of neuronal NO release, activation of ICC, and consecutive smooth muscle relaxation. ICC of the DMP seem to be the primary targets for neurally released NO.

Animals↗
PubMed2005

Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways.

Dendritic arborization and spine formation are critical for the functioning of neurons. Although many proteins have been identified recently as regulators of dendritic morphogenesis, the intracellular signaling pathways that control these processes are not well understood. Here we report that the Ras-phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway plays pivotal roles in the regulation of many aspects of dendrite formation. Whereas the PI3K-Akt-mTOR pathway alone controlled soma and dendrite size, a coordinated activation together with the Ras-mitogen-activated protein kinase signaling pathway was required for increasing dendritic complexity. Chronic inhibition of PI3K or mTOR reduced soma and dendrite size and dendritic complexity, as well as density of dendritic filopodia and spines, whereas a short-term inhibition promoted the formation of mushroom-shaped spines on cells expressing constitutively active mutants of Ras, PI3K, or Akt, or treated with the upstream activator BDNF. Together, our data underscore the central role of a spatiotemporally regulated key cell survival and growth pathway on trophic regulation of the coordinated development of dendrite size and shape.

Animals↗
PubMed2003

The reelin signaling pathway: some recent developments.

The Reelin signaling pathway plays a key role in the architectonic development of the central nervous system. Extracellular Reelin binds to receptors of the lipoprotein receptor family and induces tyrosine phosphorylation of the adaptor Dab1. In this paper, we discuss three recent developments. First, we show that the central part of Reelin is involved in receptor binding and signal activation as reflected in Dab1 phosphorylation. Second, we examine the genomic organization, alternative splicing and promoter use of the Dab1 gene, which hint at a particularly complex regulation. Third, we present preliminary studies by in situ hybridization that demonstrate regulated expression of Reelin receptors and Dab1 by radial precursors in the ventricular zone.

Cell Adhesion Molecules, Neuronal↗
PubMed2004

[Role of nitric oxide--NF-kappaB signaling pathway in differentiation of human naive T lymphocytes into Th1/Th2 cells].

AIM: To explore the role of nitric oxide (NO)--NF-kappaB signaling pathway in the differentiation of human naive T lymphocytes into Th1/Th2 cells. METHODS: Human naive T lymphocytes were isolated from umbilical blood. Various concentrations of NO donor sodium nitroprusside (SNP), NO inhibitor NAME and NF-kappaB inhibitor PDTC were added to the culture medium to induce the differentiation of naive T cells towards Th1/Th2 cells. The expressions of intracellular cytokine IFN-gamma and IL-4 were detected by flow cytometry. RESULTS: The treatment of SNP, NAME and PDTC made no difference on the percentage of cells expressing IFN-gamma (Th1) or IL-4 (Th2) in comparison with that of the control group (P < 0.05). CONCLUSION: Signaling pathway of NO--NF-kappaB had no effect on differentiation of human naive T lymphocytes into Th1 and Th2 cells. The role of NO--NF-kappaB signaling pathway in the regulation of types 1 and 2 cytokines may occur mainly at the level of mature Th cells.

Cell Differentiation↗
PubMed2001

Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway.

C. elegans insulin-like signaling regulates metabolism, development, and life span. This signaling pathway negatively regulates the activity of the forkhead transcription factor DAF-16. daf-16 encodes multiple isoforms that are expressed in distinct tissue types and are probable orthologs of human FKHRL1, FKHR, and AFX. We show that human FKHRL1 can partially replace DAF-16, proving the orthology. In mammalian cells, insulin and insulin-like growth factor signaling activate AKT/PKB kinase to negatively regulate the nuclear localization of DAF-16 homologs (reviewed in ). We show that the absence of AKT consensus sites on DAF-16 is sufficient to cause dauer arrest in daf-2(+) animals, proving that daf-16 is the major output of insulin signaling in C. elegans. FKHR, FKRHL1, and AFX may similarly be the major outputs of mammalian insulin signaling. daf-2 insulin signaling, via AKT kinases, negatively regulates DAF-16 by controlling its nuclear localization. Surprisingly, we find that daf-7 TGF-beta signaling also regulates DAF-16 nuclear localization specifically at the time when the animal makes the commitment between diapause and reproductive development. daf-16 function is supported by the combined action of two distinct promoter/enhancer elements, whereas the coding sequences of two major DAF-16 isoforms are interchangeable. Together, these observations suggest that the combined effects of transcriptional and posttranslational regulation of daf-16 transduce insulin-like signals in C. elegans and perhaps more generally.

Animals↗
PubMed1998

Suppressor of fused links fused and Cubitus interruptus on the hedgehog signalling pathway.

The Hedgehog (Hh) family of signalling proteins [1] mediate inductive interactions either directly or by controlling the transcription of other secreted proteins through the action of Gli transcription factors, such as Cubitus interruptus (Ci) [2]. In Drosophila, the transcription of Hh targets requires the activation of the protein kinase Fused (Fu) and the inactivation of both Suppressor of fused (Su(fu)) and Costal-2 (Cos-2) [3]. Fu is required for Hh signalling in the embryo and in the wing imaginal disc and acts also as an antitumorigen in ovaries [4]. All fu- phenotypes are suppressed by the loss of function of Su(fu) [5]. Fu, Cos-2 and Ci are co-associated in vivo in large complexes that are bound to microtubules in a Hh-dependent manner [6,7]. Here we investigate the role of Su(fu) in the intracellular part of the Hh signalling pathway. Using the yeast two-hybrid method and an in vitro binding assay, we show that Su(fu), Ci and Fu can interact directly to form a trimolecular complex, with Su(fu) binding to both its partners simultaneously. Su(fu) and Ci also co-immunoprecipitate from embryo extracts. We propose that, in the absence of Hh signalling, Su(fu) inhibits Ci by binding to it and that, upon reception of the Hh signal, Fu is activated and counteracts Su(fu), leading to the activation of Ci.

Animals↗
PubMed2003

The role of adaptor protein Ste50-dependent regulation of the MAPKKK Ste11 in multiple signalling pathways of yeast.

In Saccharomyces cerevisiae, Ste50 functions in cell signalling between the activated G protein and the mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) Ste11. ScSte50 is an essential component of three MAPK-mediated signalling pathways, which control the mating response, invasive/filamentous growth and osmotolerance (HOG pathway), respectively. ScSte50 signalling may also contribute to cell wall integrity in vegetative cells. The protein contains a sterile alpha motif (SAM) and a putative Ras-associated domain (RAD), which are essential for signal transduction. Ste50 and Ste11 interact constitutively via their SAM regions. Ste50 interacts weakly and probably transiently with the pheromone receptor-bound heterotrimeric G protein G(alpha beta gamma), and with the small G proteins Cdc42, Ras1 and Ras2. It is specifically the RAD region of Ste50 that mediates the interactions with Cdc42 and Ras. Homologues of ScSTE50 are also found in other fungi, like S. kluyveri, Hansenula polymorpha, Candida albicans and Neurospora crassa. In this review, the role of Ste50 as an adaptor that links the G protein-associated Cdc42-Ste20 kinase complex to the effector kinase Ste11 and thus modulates signal transduction, especially in the pheromone-response pathway of S. cerevisiae, is discussed.

Amino Acid Sequence↗
PubMed2004

Ca(2+)-calmodulin signalling pathway up-regulates GABA synaptic transmission through cytoskeleton-mediated mechanisms.

We investigated the role of calcium (Ca(2+))/calmodulin (CaM) signaling pathways in modulating GABA synaptic transmission at CA1 pyramidal neurons in hippocampal slices. Whole-cell pipettes were used to record type A GABA receptor (GABA(A)R)-gated inhibitory postsynaptic currents (IPSCs) and to perfuse intracellularly modulators in the presence of glutamate receptor antagonists. GABA(A)R-gated IPSCs were enhanced by the postsynaptic infusions of adenophostin (1 microM), a potent agonist of inositol-1,4,5-triphosphate receptor (IP(3)R) that induces Ca(2+) release. The enhancement was blocked by co-infusing either 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (10 mM) or CaM-binding peptide (100 microM). Moreover, the postsynaptic infusion of Ca(2+)-CaM (40/10 microM) enhanced both evoked and spontaneous GABA(A)R-gated IPSCs. The enhancement was attenuated by co-infusing 100 microM CaM-KII(281-301), an autoinhibitory peptide of CaM-dependent protein kinases. These results indicate that postsynaptic Ca(2+)-CaM signaling pathways essentially enhance GABAergic synaptic transmission. In the investigation of synaptic targets for the enhancement, we found that IP(3)R agonist-enhanced GABA(A)R-gated IPSCs were attenuated by co-infusing colchicine (30 microM), vincristine (3 microM) or cytochalasin D (1 microM) that inhibits tubulin or actin polymerization, implying that actin filament and microtubules are involved. We conclude that postsynaptic Ca(2+)-CaM signaling pathways strengthen the function of GABAergic synapses via a cytoskeleton-mediated mechanism, probably the recruitment of receptors in the postsynaptic membrane.

Animals↗
PubMed2006

4-NQO induces apoptosis via p53-dependent mitochondrial signaling pathway.

4-Nitroquinoline N-oxide (4-NQO) as an UV-mimetic agent leading to DNA damage is a potent mutagen and carcinogen, and can induce apoptosis in various types of cells. However, the mechanism of apoptosis induced by 4-NQO is still not quite clarified. In this study we found that 4-NQO could not only induce apoptosis in KB cells, but also caused considerable damage to the mitochondrial membrane. Therefore, we inferred that 4-NQO might induce apoptosis through the mitochondrial signaling pathway resulting from DNA damage. Further investigation showed that the apoptosis induced by 4-NQO was p53-dependent. Furthermore, the expression levels of bax and bcl-2, closely related to mitochondrial signaling pathway, were up- and down-regulated, respectively. Meanwhile, the activity of caspase-9 and -3, lying in downstream of mitochondrial, was also enhanced. At the same time, the expression level of p21 also was increased by 4-NQO exposure, leading to the cell cycle arrested in G(1) phase. The results indicated that 4-NQO arrested cell cycle in G(1) phase, thus allowing enough time for DNA repair; on the other hand, if the cellular DNA were not repaired, apoptosis may follow through the p53-dependent mitochondrial signaling pathway, and mechanism of apoptosis induced by 4-NQO is not exactly the same that induced by UV radiation, as the later induces apoptosis through death receptors and mitochondrial signaling pathway.

4-Nitroquinoline-1-oxide↗
PubMed2000

Dual role of signaling pathways leading to Ca(2+) and cyclic AMP elevation in host cell invasion by Trypanosoma cruzi.

Cell invasion by the protozoan parasite Trypanosoma cruzi involves activation of host signaling pathways and the recruitment and fusion of lysosomes at the parasite entry site. A major signaling pathway regulating invasion of fibroblasts, epithelial cells, and myoblasts involves mobilization of Ca(2+) from intracellular stores and requires the activity of a T. cruzi serine peptidase, oligopeptidase B (OPB). Deletion of the OPB gene results in a marked defect in trypomastigote virulence, consistent with a greatly reduced cell invasion capacity. Here we show that uptake by macrophages, on the other hand, is largely independent of OPB expression and sensitive to inhibition of by cytochalasin D. The residual invasion capacity of OPBnull trypomastigotes in fibroblasts still involves lysosome recruitment, although in a significantly delayed fashion. Transient elevations in intracellular Ca(2+) concentrations were observed in host cells exposed to both wild-type and OPBnull trypomastigotes, but the signals triggered by the mutant parasites were less vigorous and delayed. The capacity of triggering elevation in host cell cyclic AMP (cAMP), however, was unaltered in OPBnull trypomastigotes. Modulation in cAMP levels preferentially affected the residual cell invasion capacity of OPBnull parasites, suggesting that this signaling pathway can play a dominant role in promoting cell invasion in the absence of the major OPB-dependent pathway.

Actins↗
PubMed2001

Nuclear localization of Duplin, a beta-catenin-binding protein, is essential for its inhibitory activity on the Wnt signaling pathway.

Duplin binds to beta-catenin and inhibits the Wnt signaling pathway, thereby leading to repression of the beta-catenin-mediated transactivation and Xenopus axis formation. To find an additional function of Duplin, yeast two-hybrid screening was carried out. Importin alpha was isolated as a binding protein of Duplin. Importin alpha bound directly to basic amino acid clusters of Duplin. Although Duplin was present in the nucleus, deletion of the basic amino acid clusters (Duplin(Delta 500-584)) retained Duplin in the cytoplasm. Duplin(Delta 500-584) bound to beta-catenin as efficiently as wild-type Duplin, but it neither repressed Wnt-dependent Tcf transcriptional activation in mammalian cells nor showed ventralization in Xenopus embryos. The Duplin mutant without a beta-catenin-binding region lost the ability to inhibit the Wnt-dependent Tcf activation, but retained its ventralizing activity. Furthermore, Duplin not only suppressed beta-catenin-dependent axis duplication and expression of siamois, a Wnt-regulated gene, but also inhibited siamois-dependent axis duplication. These results indicate that Duplin is translocated to the nucleus by interacting with importin alpha, and that nuclear localization is essential for the function of Duplin. Moreover, Duplin has an additional activity of inhibiting the Wnt signaling pathway by affecting the downstream beta-catenin target genes.

Active Transport, Cell Nucleus↗
PubMed2006

Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4.

The role of the TGF-beta-Smad signaling pathway in the carcinogenesis of head and neck cancer has not been fully evaluated genetically. In this study, we screened for mutation in the five main members of the TGF-beta -Smad signaling pathway, TGF-beta type I receptor (TGFBRI), TGF-beta type II receptor (TGFBRII), SMAD2, SMAD3 and SMAD4, in eight human head and neck squamous cell carcinoma (HNSCC) cell lines. Two mutations with presumed loss of heterozygosity (LOH) were identified. A novel missense mutation of SMAD2, located in exon 8 at codon 276 TCG (ser) -->TTG (leu), was identified in cell line SCC-15. This is the first report of a biallelic mutation of the SMAD2 gene in HNSCC. A nonsense mutation of the SMAD4 gene in exon 5 codon 245 CAG (glut) -->TAG (stop) was found in cell line CAL27. Western blotting verified that this nonsense mutation gives rise to the complete loss of the Smad4 protein in the cells. While the down-regulation and loss of expressions of the TGF-beta-Smad signaling pathway have been described frequently in HNSCC, here we offer further genetic evidence that the pathway is directly targeted for mutation during the HNSCC tumorigenesis.

Activin Receptors, Type I↗
PubMed2003

Microarray analysis of somitogenesis reveals novel targets of different WNT signaling pathways in the somitic mesoderm.

WNT signaling plays a major role in patterning the dermomyotome of the somitic mesoderm. However, knowledge of downstream target genes and their regulation is limited. To identify new genes involved in the development and early patterning of the somite, we performed a comparison of gene expression by microarray between the presomitic mesoderm and the 5 most recently formed somites of the mouse at embryonic day 9.5. We identified 207 genes upregulated and 120 genes downregulated in somite formation. Expression analysis and functional categorization of these genes demonstrate this to be a diverse pool that provides a valuable resource for studying somite development. Thus far, we have found three genes expressed in the dermomyotome of the early somite. Consistent with their expression patterns, these genes are transcriptional targets of WNT signals, but display differential activation by different WNTs. We further demonstrate that 1 of these genes, Troy, is a direct target of canonical WNT signaling, while the other 2 genes, Selp and Arl4, are not. Thus, our microarray study using microdissected tissues not only provides global information on gene expression during somite development, it also provides novel targets to study the inductive signaling pathways that direct somite patterning.

Adenoviridae↗
PubMed1994

Docosahexaenoic acid and signaling pathways in rabbit colon.

The effects of one of the main components of fish oil, docosahexaenoic acid (DHA), on prostaglandin (PG) and Ca2+ signaling pathways were examined in intact mucosa and freshly isolated crypt cells of rabbit descending colon. Preincubation of serosal mucosa for 20 min with 1 microM DHA fully suppressed the short-circuit and transepithelial conductance increase induced by serosal addition of 10 microM arachidonic acid (AA). DHA at 1 microM also prevented the Cl- secretion promoted by 10 microM AA, as estimated by unidirectional 36Cl flux measurements (net flux = 0.68 +/- 0.30 versus -1.91 +/- 0.20 microEq/hr/cm2, four experiments, p < 0.001), whereas it did not affect the electrophysiological and ion flux responses to PGE2. Addition of 1 microM DHA to the serosal side of the mucosa also inhibited the PG cascade activation elicited by AA (PG synthesis and second messenger cAMP increase). In vitro assays of colonic cyclooxygenase activity showed that 1 microM DHA inhibited (with a 20-min lag) cyclooxygenase activity to the same extent as 5 microM indomethacin (approximately 82% and 80%, respectively). DHA also affected the Ca2+ signaling pathway; in isolated crypt cells, the cytosolic free Ca2+ concentration ([Ca2+]i) dropped by 49 +/- 7.6% (mean +/- standard error, six experiments) after incubation with 1 microM DHA. The sustained phase of the [Ca2+]i response to 500 nM concentrations of the intracellular Ca(2+)-ATPase inhibitor thapsigargin was also inhibited within 150 sec upon 1 microM DHA addition (141 +/- 5.8 versus 243 +/- 8.2 nM [Ca2+]i mean +/- standard error, eight experiments, p < 0.01). The [Ca2+]i-lowering effect of DHA, which was not achieved by incubation with other free fatty acids, was not prevented by removal of Na+ from the incubation medium (-46 +/- 4.3% versus -47 +/- 3.8%, mean +/- standard error, four experiments), nor it was mediated by cAMP-, protein kinase C-, or calmodulin-dependent mechanisms. The incubation of highly purified basolateral membranes of crypt cells with 1 microM DHA for 1 min produced a 5-fold increase (IC50 = 0.25 microM) in the plasma membrane Ca(2+)-ATPase activity (34.3 +/- 2.73 versus 6.02 +/- 0.50 nmol/mg of protein/min, mean +/- standard error, four experiments, p < 0.0001), thus indicating that the DHA effects on the Ca2+ pathway were mediated mainly by an increase in plasma membrane Ca2+ pump activity. These findings suggest that DHA is a powerful modulator of the cellular response to activation of PG and Ca2+ signaling pathways.

Animals↗
PubMed2006

Gefitinib and the modulation of the signaling pathways downstream of epidermal growth factor receptor in human liver cancer cells.

BACKGROUND: The transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGFR) signaling pathway has been demonstrated to have a pivotal role in hepatocarcinogenesis. We examined whether abrogation of the TGF-alpha/EGFR signaling pathway with a selective EGFR tyrosine kinase inhibitor, gefitinib, could inhibit the proliferation of human hepatocellular carcinoma (HCC) cells. METHODS: Cellular growth was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Cell-cycle distribution was analyzed by flow cytometric analysis. Activities of signaling molecules were evaluated by Western blot analysis. RESULTS: HCC cells expressed EGFR at variable levels; however, extracellular signal-regulated kinase (ERK)1/2 and AKT, key signaling molecules downstream of EGFR, were not constitutively active in the cells. When HCC cells were treated with TGF-alpha, cellular growth was accelerated in a manner dependent on activation of ERK1/2 and AKT. When the cells were co-treated with gefitinib and TGF-alpha, enhanced proliferation and activation of ERK1/2 and AKT were canceled, and the cell-cycle promotion by TGF-alpha was inhibited by co-treatment with gefitinib and TGF-alpha, independently of expression levels of EGFR. In contrast, gefitinib did not show an antiproliferative effect on HCC cells cultivated under the 10% serum condition. CONCLUSIONS: The present data demonstrated that gefitinib exerted an antiproliferative action on HCC cells under a limited condition when signaling pathways downstream of EGFR were activated by TGF-alpha.

ErbB Receptors↗