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At least 613 records · Page 34Linked to original sources
PubMed2006

Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway.

OBJECTIVE: We tested whether ischemic postconditioning (IPostC) is protective in remodeled myocardium. METHODS: Post-myocardial infarct (MI)-remodeled hearts after permanent coronary artery ligation and one kidney one clip (1K1C) hypertensive hearts of male Wistar rats were exposed to 40 min of ischemia followed by 90 min of reperfusion. IPostC was induced by six cycles of 10 s reperfusion interspersed by 10 s of no-flow ischemia. Activation of reperfusion injury salvage kinases was measured using Western blotting and in vitro kinase activity assays. RESULTS: IPostC prevented myocardial damage in both MI-remodeled and 1K1C hearts, as measured by decreased infarct size and lactate dehydrogenase release, and improved function. The reduction in infarct size and the recovery of left ventricular contractility achieved by IPostC was less in 1K1C hearts, but was unchanged in MI-remodeled hearts when compared to healthy hearts. In contrast, the recovery of inotropy was unaffected in 1K1C hearts, but was less in MI-remodeled hearts. Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway with LY294002 abolished the protective effects of IPostC on both disease models and healthy hearts. Western blot analysis in conjunction with in vitro kinase activity assays identified protein kinase B (PKB)/Akt but not p42/p44 extracellular-signal regulated kinase 1/2 (ERK1/2) as the predominant kinase in IPostC-mediated cardioprotection in remodeled hearts. IPostC increased phosphorylation of the PKB/Akt downstream targets eNOS, GSK3beta, and p70S6K in remodeled hearts. CONCLUSION: Our results offer evidence that IPostC mediates cardioprotection in the remodeled rat myocardium primarily via activation of the PI3K-PKB/Akt reperfusion injury salvage kinase pathway.

Actins↗
PubMed2006

Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.

Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL)-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP) is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida-induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida-induced cytokine production through the inhibition of NFkappaB. Consistently, macrophages lacking SHIP displayed enhanced NFkappaB-driven gene transcription, whereas overexpression of SHIP led to decreased NFkappaB activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFkappaB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.

Animals↗
PubMed2001

FYVE domain targets Pib1p ubiquitin ligase to endosome and vacuolar membranes.

Signaling by phosphatidylinositol 3-kinases (PI3Ks) is often mediated by proteins which bind PI3K products directly and are localized to intracellular membranes rich in PI3K products. The FYVE finger domain binds with high specificity to PtdIns3P and proteins containing this domain have been shown to be important components of diverse PI3K signaling pathways. The genome of the yeast Saccharomyces cerevisiae encodes five proteins containing FYVE domains, including Pib1p, whose function is unknown. In addition to a FYVE finger motif, the primary structure of Pib1p contains a region rich in cysteine and histidine residues that we demonstrate binds 2 mol eq of zinc, consistent with this region containing a RING structural domain. The Pib1p RING domain exhibited E2-dependent ubiquitin ligase activity in vitro, indicating that Pib1p is an E3 RING-type ubiquitin ligase. Fluorescence microscopy was used to demonstrate that a GFP-Pib1p fusion protein localized to endosomal and vacuolar membranes and deletional analysis of Pib1p domains indicated that localization of GFP-Pib1p is mediated solely by the FYVE domain. These results suggest that Pib1p mediates ubiquitination of a subset of cellular proteins localized to endosome and vacuolar membranes, and they expand the repertoire of PI3K-regulated pathways identified in eukaryotic cells.

Amino Acid Motifs↗
PubMed2003

Phenotypic switching of VEGF and collagen XVIII during hypoxia in head and neck squamous carcinoma cells.

The present study sought to determine the potential role of stress activated MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating phenotypic switching between angiogenic and angiostatic elements among squamous cell carcinoma (SCC) cell lines. In particular, we investigated the effects of hypoxia and those of cobalt chloride (CoCl(2)), which mimics the hypoxic response including the production of reactive oxygen species, on such phenotypic shifts. The expression and production of collagen XVIII, and CBP2/Hsp47 provided a measure of an angiostatic phenotype, while vascular endothelial growth factor (VEGF) expression was used to assess potential angiogenic states. These studies revealed that hypoxia produced a slight up-regulation of collagen XVIII and CBP2/Hsp47 that was inhibited by the stress kinase inhibitor SB203580 but was unaffected by N-acetylcysteine (NAC). In addition, VEGF expression was increased following hypoxia and this effect was reversed with inhibition of by SB203580. Conversely, CoCl(2) significantly diminished the expression of both collagen XVIII and CBP2/Hsp47 and enhanced VEGF expression. These changes were reversed by the PI3K inhibitor wortmannin and by treating cells with NAC. These studies show that phenotypic switching between collagen XVIII and VEGF is controlled by stress activated kinases under hypoxia, and PI3K signaling pathways as well as reactive oxygen species (ROS) following CoCl(2) treatment. Furthermore, modulation of the angiogenic switch is most profound during Akt activation than during activation of stress activated kinases.

Acetylcysteine↗
PubMed2005

Ras initiates phosphatidyl-inositol-3-kinase (PI3K)/PKB mediated signalling pathways in untransformed human peripheral blood T lymphocytes.

Activation of T lymphocytes through costimulation of the T cell receptor/CD3 complex (TCR/CD3) and coreceptors (e.g. CD2 or CD28) leads to production of the growth factor interleukin-2 (IL-2) and subsequent proliferation. For these activation processes, remodelling of the actin cytoskeleton plays an important functional role. We have shown that the activity of the actin-remodelling protein cofilin is crucially involved in T lymphocyte activation processes. In unstimulated human peripheral blood T lymphocytes (PB-T) cofilin exists in its inactive ser-3-phosphorylated form. T lymphocyte activation through costimulation of TCR plus the coreceptors CD28 or CD2, respectively, induces the dephosphorylation of cofilin. Concomitantly, cofilin associates with the actin cytoskeleton. The functional importance of cofilin for T lymphocyte activation was shown employing cell permeable peptides which block binding of cofilin to actin. In human PB-T these peptides impair the formation of the immunological synapse and inhibit the induction of T lymphocyte proliferation and cytokine production. The serine phosphatases PP1 and PP2A dephosphorylate cofilin in T lymphocytes. Importantly, a PKC-Ras-MEK/PI3K-cascade links costimulation of PB-T through TCR/CD3 and CD28 to activation of cofilin through dephosphorylation. Notably, the induction of cofilin dephosphorylation requires the combined activities of two Ras-effectors, namely MEK and PI3K. With respect to PI3K, this result was unexpected since so far it was generally assumed that-unlike in other cell types-Ras is not able to activate PI3K in T lymphocytes, as concluded from experiments performed with the human T-lymphoma line Jurkat. This discrepancy implied that the signalling events upstream of PI3K differ between PB-T and Jurkat cells. In line with this, we found that in PB-T the PI3K-inhibitors wortmannin and LY294002 block activation induced cofilin dephosphorylation and its association with the actin cytoskeleton. In Jurkat cells, however, where cofilin is present mainly in its non-phosphorylated form and permanently associated with the actin cytoskeleton, wortmannin and LY294002 do not block these events. Studies by others employing these PI3K-inhibitors have also led to such contradictory results: While in stimulated PB-T these inhibitors repress expression of IL-2, they even enhance IL-2 expression in Jurkat cells. These findings show that signalling events in Jurkat cells are not representative for signalling processes in untransformed human T lymphocytes. Importantly, our data demonstrate that-rebutting a persistent dogma-a T-cell specific uncoupling of PI3K from Ras does not exist.

Actin Depolymerizing Factors↗
PubMed2003

Affinity with Raf is sufficient for Ras to efficiently induce rat mammary carcinomas.

The role of three major Ras downstream effector pathways in the induction of mammary cancer was studied using an in situ mammary ductal gene delivery model. Replication-defective retroviral vectors were used to infect endogenous rat mammary epithelial cells with three individual Ras effector loop mutants, each of which transduces its signal through a different Ras effector pathway (Raf, PI3K or RalGDS). Several groups have used Ras effector loop mutants in cultured cells, clearly characterizing the signaling specificity of each over a wide range of cell lines and conditions. Each of the three Ras effector loop mutations impairs Ras for neoplastic transformation of immortal cell lines in culture. In contrast, when evaluated in vivo by infecting endogenous rat mammary epithelial cells in situ with retroviral vectors, we find that codon 12 mutant activated V12-Ras and all three V12-Ras effector loop mutants individually induce mammary carcinomas. Most notably, a Ras effector loop mutant that lacks affinity with PI3K and RalGDS but retains affinity with Raf (E38-V12-Ras) is relatively similar in potency to V12-Ras for mammary carcinoma induction. Two other Ras effector loop mutants, each lacking affinity with Raf, one retaining affinity with PI3K (C40-V12-Ras), the other with RalGDS (G37-V12-Ras), resulted in much longer tumor latency than E38-V12-Ras and V12-Ras and a reduced carcinoma frequency. Tumor latencies for V12-Ras, E38-V12-Ras, C40-V12-Ras and G37-V12-Ras were 4, 4, 11 and 12 weeks, respectively. We conclude that the Ras-Raf pathway can function independently of the Ras-PI3K and Ras-RalGDS pathways for rapid induction of rat mammary carcinomas, while Ras-PI3K and Ras-RalGDS pathways may also individually induce mammary carcinomas following a long latency.

3T3 Cells↗
PubMed1998

Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation.

The phosphatidylinositol 3-kinase (PI3K)-signaling pathway has emerged as an important component of cytokine-mediated survival of hemopoietic cells. Recently, the protein kinase PKB/akt (referred to here as PKB) has been identified as a downstream target of PI3K necessary for survival. PKB has also been implicated in the phosphorylation of Bad, potentially linking the survival effects of cytokines with the Bcl-2 family. We have shown that granulocyte/macrophage colony-stimulating factor (GM-CSF) maintains survival in the absence of PI3K activity, and we now show that when PKB activation is also completely blocked, GM-CSF is still able to stimulate phosphorylation of Bad. Interleukin 3 (IL-3), on the other hand, requires PI3K for survival, and blocking PI3K partially inhibited Bad phosphorylation. IL-4, unique among the cytokines in that it lacks the ability to activate the p21ras-mitogen-activated protein kinase (MAPK) cascade, was found to activate PKB and promote cell survival, but it did not stimulate Bad phosphorylation. Finally, although our data suggest that the MAPK pathway is not required for inhibition of apoptosis, we provide evidence that phosphorylation of Bad may be occurring via a MAPK/ERK kinase (MEK)-dependent pathway. Together, these results demonstrate that although PI3K may contribute to phosphorylation of Bad in some instances, there is at least one other PI3K-independent pathway involved, possibly via activation of MEK. Our data also suggest that although phosphorylation of Bad may be one means by which cytokines can inhibit apoptosis, it may be neither sufficient nor necessary for the survival effect.

Apoptosis↗
PubMed2004

Thrombin and histamine stimulate endothelial nitric-oxide synthase phosphorylation at Ser1177 via an AMPK mediated pathway independent of PI3K-Akt.

Histamine and thrombin cause phosphorylation and activation of endothelial NO-synthase (eNOS) on Ser1177. We tested the role of various protein kinases in mediating this effect in human umbilical vein endothelial cells. Inhibition of the Ca2+/calmodulin-dependent protein kinase II or phosphoinositide 3-kinase (PI3K) had no effect. H89, an inhibitor of both protein kinase A (PKA) and 5'-AMP-activated protein kinase (AMPK), strongly inhibited phosphorylation and activity of eNOS. Conversely, the PKA inhibitor Rp-adenosine 3 '5'-cyclic monophosphate (cAMPS) had no effect and eNOS was not phosphorylated by treatments that affect cAMP levels. Thrombin and histamine caused phosphorylation of AMPK on Thr172 as well as on its downstream target acetyl-CoA carboxylase. Activation of AMPK using AICAR or CCCP also resulted in eNOS phosphorylation. We conclude that histamine and thrombin cause eNOS phosphorylation in an AMPK mediated manner, independent of P13K-Akt.

AMP-Activated Protein Kinases↗
PubMed2006

All-trans retinoic acid antagonizes UV-induced VEGF production and angiogenesis via the inhibition of ERK activation in human skin keratinocytes.

Incident UV radiation leads to the upregulation of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in human skin. However, the molecular basis of UV-induced angiogenesis in skin remains to be elucidated. In this study, we investigated the roles of UV exposure on cutaneous angiogenesis, its associated signaling mechanisms, and the effect of all-trans retinoic acid (tRA) on UV-induced vascularization, and VEGF expression. Using a human epidermal cell line, HaCaT, we found that UV induces VEGF mRNA and protein expression via the MAPK/ERK kinase-ERK1/2 (extracellular signal-regulated kinase 1/2) pathway but not via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and that tRA pretreatment significantly inhibits UV-induced VEGF overexpression and ERK1/2 activation. In human skin in vivo, we confirmed that skin vascularization significantly increased after a single exposure to UV, as was evidenced by a prominent increase in vessel size, vascular density, and in the cutaneous area occupied by vessels, and we found that these events are associated with VEGF upregulation. Topical pretreatment with tRA under occlusion inhibited not only UV-induced VEGF upregulation and angiogenesis with a significant reduction of vessel density but also UV-induced ERK1/2 activation in human skin. Collectively, our data demonstrate that tRA inhibits the UV-induced angiogenic switch via downmodulation of ERK1/2 activation and consecutive VEGF overexpression. These findings may help us understand the molecular mechanisms that regulate skin angiogenesis due to UV exposure, and provide evidence of the potential of tRA in terms of preventing angiogenesis-associated skin damage following exposure to UV irradiation.

Adult↗
PubMed2006

Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.

Adult↗
PubMed2006

Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro.

Human esophageal cancers have been shown to express high levels of epidermal growth factor receptor (EGFR) and a relationship between high EGFR expression and local advance, the number of lymph node metastases, life expectancy, and sensitivity to chemo-radiotherapy has been demonstrated. We examined the use of gefitinib, an orally active EGFR-selective tyrosine kinase inhibitor, as a new strategy for treatment of esophageal carcinoma. The effects of gefitinib were evaluated in monotherapy and in combination with radiotherapy in human esophageal carcinoma cell lines. Gefitinib produced a dose-dependent inhibition of cellular proliferation in all of the 8 esophageal carcinoma cell lines examined, with IC50 values ranging from 5.7 microM to 36.9 microM. In combination, gefitinib and radiotherapy showed a synergistic effect in 2 human esophageal carcinoma cell lines and an additive effect in 5 cell lines. Western blotting demonstrated that gefitinib blocked activation of the EGFR-extracellular signal-regulated kinase (Erk) pathway and the EGFR-phosphoinositide-3 kinase (PI3K)-Akt pathway after irradiation. These results suggest that further evaluation of EGFR blockade as a treatment for esophageal cancer should be performed, and that radiotherapy combined with EGFR blockade may enhance the response of esophageal carcinoma to therapy.

Animals↗
PubMed2003

Integrin-dependent cell growth and survival are mediated by different signals in thyroid cells.

Cell adhesion to extracellular matrix regulates proliferation and survival of several cell types including epithelial thyroid cells. Activation of integrin receptors by binding to extracellular matrix generates a complex cell type-dependent signaling. Adhesion to extracellular matrix induces proliferation and survival in primary cultures of thyroid cells and induces survival in immortalized human thyrocytes. In this study we demonstrate that in immortalized human thyrocyte cells, adhesion to immobilized fibronectin (FN) stimulates DNA synthesis and proliferation through the p21Ras/MAPK pathway, whereas cell survival is mediated by phosphatidylinositol 3-kinase (PI3K) signal pathway. Integrin activation by immobilized FN induced phosphorylation of pp125 focal adhesion kinase and paxillin and induced the formation of focal adhesion kinase/Grb-2/Sos complex. Western blot and in vitro kinase assay demonstrated the activation of Ras and the p44/p42 MAPK/ERK1/2. Inhibition of p21Ras activity and inhibition of MAPK enzymatic activity completely arrested cell growth but did not induce cell death. Integrin activation by cell adhesion to FN also induced activation of PI3K. Inhibition of PI3K enzymatic activity induced apoptosis demonstrated by annexin V-binding assay and loss of cellular DNA content. These results demonstrate that in thyroid cells adhesion to FN regulates proliferation through the p21Ras/MAPK signal pathway, whereas integrin-mediated cell survival is mediated by PI3K.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 2: PI3K/Akt/PTEN, mTOR, SHH/PTCH and angiogenesis.

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targeted therapy. Activity of the phosphoinositide 3; kinase (PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimulation by growth factor receptors and Ras. Loss of function of the tumor suppressor gene PTEN also frequently contributes to upregulation of PI3K/Akt. Several compounds, such as wortmannin and LY-294002, can target PI3K and inhibit activity of this pathway. The mammalian target of rapamycin (mTOR) is an important regulator of cell growth and metabolism and is often upregulated by Akt. Clinical trials of CCI-779, an inhibitor of mTOR, are ongoing in recurrent malignant glioma patients. The sonic hedgehog/PTCH pathway is involved in the tumorigenesis of some familial and sporadic medulloblastomas. This pathway can be targeted by cyclopamine, which is under evaluation in preclinical studies. Angiogenesis is a critical process for development and progression of brain tumors. Targeted approaches to inhibit angiogenesis include monoclonal antibodies, receptor tyrosine kinase inhibitors, antisense oligonucleotides and gene therapy. Clinical trials are ongoing for numerous angiogenesis inhibitors, including thalidomide, CC-5103 and PTK 787/ZK 222584. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.

Angiogenesis Inhibitors↗
PubMed2005

Estrogen receptor alpha binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor gamma signaling in breast cancer cells.

PURPOSE: The molecular mechanisms involved in the repressive effects exerted by estrogen receptors (ER) on peroxisome proliferator-activated receptor (PPAR) gamma-mediated transcriptional activity remain to be elucidated. The aim of the present study was to provide new insight into the crosstalk between ERalpha and PPARgamma pathways in breast cancer cells. EXPERIMENTAL DESIGN: Using MCF7 and HeLa cells as model systems, we did transient transfections and electrophoretic mobility shift assay and chromatin immunoprecipitation studies to evaluate the ability of ERalpha to influence PPAR response element-mediated transcription. A possible direct interaction between ERalpha and PPARgamma was ascertained by co-immunoprecipitation assay, whereas their modulatory role in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway was evaluated by determining PI3K activity and AKT phosphorylation. As a biological counterpart, we investigated the growth response to the cognate ligands of both receptors in hormone-dependent MCF7 breast cancer cells. RESULTS: Our data show for the first time that ERalpha binds to PPAR response element and represses its transactivation. Moreover, we have documented the physical and functional interactions of ERalpha and PPARgamma, which also involve the p85 regulatory subunit of PI3K. Interestingly, ERalpha and PPARgamma pathways have an opposite effect on the regulation of the PI3K/AKT transduction cascade, explaining, at least in part, the divergent response exerted by the cognate ligands 17beta-estradiol and BRL49653 on MCF7 cell proliferation. CONCLUSION: ERalpha physically associates with PPARgamma and functionally interferes with PPARgamma signaling. This crosstalk could be taken into account in setting new pharmacologic strategies for breast cancer disease.

Breast Neoplasms↗
PubMed2004

The 15-deoxy-delta12,14-prostaglandin J2 inhibits the inflammatory response in primary rat astrocytes via down-regulating multiple steps in phosphatidylinositol 3-kinase-Akt-NF-kappaB-p300 pathway independent of peroxisome proliferator-activated receptor gamma.

Ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), such as 15-deoxy-12,14-PGJ2 (15d-PGJ2), have been proposed as a new class of anti-inflammatory compounds because 15d-PGJ2 was able to inhibit the induction of inflammatory response genes such as inducible NO synthase (iNOS) and TNF (TNF-alpha) in a PPAR-dependent manner in various cell types. In primary astrocytes, the anti-inflammatory effects (inhibition of TNF-alpha, IL-1beta, IL-6, and iNOS gene expression) of 15d-PGJ2 are observed to be independent of PPARgamma. Overexpression (wild-type and dominant-negative forms) of PPARgamma and its antagonist (GW9662) did not alter the 15d-PGJ2-induced inhibition of LPS/IFN-gamma-mediated iNOS and NF-kappaB activation. The 15d-PGJ2 inhibited the inflammatory response by inhibiting IkappaB kinase activity, which leads to the inhibition of degradation of IkappaB and nuclear translocation of p65, thereby regulating the NF-kappaB pathway. Moreover, 15d-PGJ2 also inhibited the LPS/IFN-gamma-induced PI3K-Akt pathway. The 15d-PGJ2 inhibited the recruitment of p300 by NF-kappaB (p65) and down-regulated the p300-mediated induction of iNOS and NF-kappaB luciferase reporter activity. Coexpression of constitutive active Akt and PI3K (p110) reversed the 15d-PGJ2-mediated inhibition of p300-induced iNOS and NF-kappaB luciferase activity. This study demonstrates that 15d-PGJ2 suppresses inflammatory response by inhibiting NF-kappaB signaling at multiple steps as well as by inhibiting the PI3K/Akt pathway independent of PPARgamma in primary astrocytes.

Animals↗
PubMed2003

Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers.

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway controls several important biological functions, such as cell growth regulation, apoptosis, and migration. However, the way in which PI3K/Akt controls androgen receptor (AR)-mediated prostate cancer cell growth remains unclear and controversial. Here, we demonstrate that the PI3K/Akt pathway regulates AR activity in a cell passage number-dependent manner. Specifically, PI3K/Akt pathway can suppress AR activity in androgen-dependent LNCaP cells with low passage numbers. In contrast, it can also enhance AR activity in LNCaP cells with high passage numbers. Furthermore, we also demonstrate that insulin-like growth factor-1 can activate the PI3K/Akt pathway that results in the phosphorylation of AR at Ser210 and Ser790. The consequence of these events may then change the stability of AR protein. Together, our results demonstrate that the PI3K/Akt pathway may have distinct mechanisms to modulate AR functions in various stages of prostate cancer cells and that a combined therapy of antiandrogens and anti-PI3K/Akt inhibitors may be worth considering as a future therapeutic approach to battle prostate cancer.

Binding Sites↗
PubMed2005

A phosphatidyl-inositol-3-kinase-dependent anti-inflammatory pathway activated by Salmonella in epithelial cells.

Salmonella activates the phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway in epithelial cells, but its role in inflammation has not been previously elucidated. We show here that inhibition of PI3K in T84 intestinal epithelial cells results in augmentation of Salmonella-induced interleukin-8 (IL-8) production at the level of both protein and mRNA. The mechanism of this effect appears to involve altered activation of the extracellular growth factor-regulated kinase (ERK), a molecule that is implicated in the regulation of IL-8 expression. These results identify activation of the PI3K/Akt pathway as an anti-inflammatory signal that may contribute to the establishment of Salmonella in the intestine.

Cell Line↗
PubMed2001

Modulation of cyclin D1 and its signaling components by the phorbol ester TPA and the tyrosine phosphatase inhibitor vanadate.

The mechanism by which 12-O-tetradecanoylphorbol-13-acetate (TPA) triggers cell-cycle progression at G1 phase in mouse embryonic fibroblast C3H 10T1/2 cells was examined. TPA treatment resulted in a temporary induction of cyclin D1 peaking at 9 h post stimulation. PD98059 (10 microM), the specific inhibitor of MAPK kinase, completely blocked TPA-stimulated cyclin D1 induction and DNA synthesis, confirming that MAPK activation plays an essential role in TPA-stimulated cell-cycle progression. Although both PKCalpha and PKCepsilon are expressed in C3H 10T1/2 cells, inhibitor studies suggest that PKCepsilon activation is required for the activation of MEK/MAPK signal transduction cascade. p70s6K, an important kinase involved in the regulation of protein synthesis and cell-cycle progression, has been reported to be activated through a PKC-dependent pathway (TPA-activatable) in addition to a PI3K-dependent pathway. Here, we demonstrate for the first time that TPA-stimulated MAPK activation is essential for the phosphorylation of several key residues involved in the activation of p70s6K, namely, thr389, thr421, and ser424. Vanadate, the tyrosine phosphatase inhibitor, triggered a sustained elevation of the level of active MAPK. However, corresponding to a rapid loss of cyclin D1 protein, vanadate treatment resulted in a significant shut out of 3H-thymidine incorporation into DNA regardless of TPA cotreatment. Vanadate treatment also led to the increase of active MEK, increased phosphorylation of p70s6K at thr389, thr421, and ser424 yet without activation of PKB. These data suggest that vanadate can selectively perturb the activation of signaling components which raises the interesting issue as to how vanadate downregulates the cyclin D1 level.

Animals↗